Binding domain for cancer-associated MUC1

Abstract

The present disclosure relates to binding domains that bind to cancer-associated MUC1, and binding moieties that comprise such binding domains. The present disclosure further relates to the use of such binding domains or binding moieties in the treatment of cancer. The present disclosure also relates to nucleic acids encoding such binding domains or binding moieties, and vectors and cells that comprise such nucleic acids.

Description

[Technical field]

[0001] The present disclosure relates to the field of binding domains and binding moieties, such as antibodies. In particular, the present disclosure relates to the field of therapeutic antibodies for the treatment of cancer. More particularly, the present disclosure relates to binding domains that bind to cancer-associated MUC1, and binding moieties that include such binding domains. [Background technology]

[0002] Mucin 1 or MUC1 is typically a transmembrane glycoprotein expressed primarily in glandular or luminal epithelial cells. MUC1 forms a physical barrier for lubrication and protection and assists in signal transduction (Shimizu M, Yamauchi KJ Biochem. 1982; 91(2): 515-24). The extracellular domain of MUC1 can extend 200-500 nm from the cell surface and is highly glycosylated. Its sugar branches are negatively charged and can oligomerize, thereby creating a physical barrier that protects the cell (Nath S, Mukherjee P. Trends Mol Med. 2014; 20(6): 332-42).

[0003] The MUC1 gene is located on chromosome 1:155,185,824-155,192,916 reverse strand (GRCh38:CM000663.2) and has 29 transcripts. MUC1 is also known under several different aliases, such as: mucin 1, cell surface associated, transmembrane, PEM, PUM, EMA, H23Ag, episialin, cancer antigen 15-3, ADMCKD(1), CD227, MCKD(1), MCD, tumor-associated epithelial membrane antigen, cancer-associated mucin, tumor-associated epithelial mucin, tumor-associated mucin. The external Ids for the MUC1 gene are HGNC:7508 NCBI; Entrez Gene:4582; Ensembl:ENSG00000185499; OMIM:158340 and UniProtKB:P15941.

[0004] The MUC1 protein consists of a single polypeptide chain that is post-translationally cleaved by autoproteolysis at the sea urchin sperm protein enterokinase and agrin (SEA) domain into two peptide subunits, designated MUC1-C and MUC-N, both of which remain associated via stable non-covalent bonds (Figure 1, Gao T. et al. Biomed Pharmacother. 2020;132:110888). MUC1-C consists of a short extracellular region with 58 amino acids, a 28 amino acid hydrophobic transmembrane region, and an intracellular cytoplasmic region with 69 amino acids. MUC1-N is located extracellularly and contains approximately 20 amino acid sequence repeats, designated as variable number tandem repeats (VNTR) (HGVTSAPDTRPAPGSTAPPA), with the number of repeats varying from 20 to 120. The VNTR is rich in serine and threonine residues, and each repeat contains five potential sites for O-glycosylation that, under normal conditions, renders MUC1 highly glycosylated with a regular pattern of O-glycosylation (Bose M, Mukherjee P. Vaccines (Basel). 2020; 8(4): 659, Zhou D. et al. Molecules. 2018; 23(6): 1326).

[0005] During malignant transformation, MUC1 is overexpressed and loses its polarity and apical distribution, with expression both at the surface and in the cytoplasm of epithelial cells. In normal cells, O-glycosylation proceeds to mature elongated branched O-glycans, but in cancer cells, these processes are disrupted. Aberrant MUC1 is characterized by incomplete glycosylation of carbohydrate side chains, leading to the formation of new carbohydrate side chains, including truncated O-glycans known as Tn antigens (GalNAcα-O-serine / threonine) and their sialylated version, sialyl-Tn antigens (STn antigens), which contain sialic acid α-2,6 linked to GalNAcα-O-serine / threonine (Figure 1, Gao T. et al. Biomed Pharmacother. 2020).

[0006] The expression of tumor-associated carbohydrates (TACAs) is involved in immune regulation and inhibition of anti-cancer immune responses, and the expression of sialic acid-containing glycans in tumor cells correlates with metastatic phenotype and poor prognosis in patients (Rodrigues Mantuano N.et al.J Immunother Cancer.2020;8(2):e001222, Bhatia R.et al.Cancer Metastasis Rev.2019;38(1-2):223-236, Anandkumar A, Devaraj H.Scand J Immunol.2013;78(1):1-7, Baldus SE.et al.Tumour Biol.1998;19(6):445-53). Tn and STn antigens are typically expressed at high levels in certain tumor cell tissues, including gastric cancer (Moreira IB. et al. Cells. 2020; 9(2): 264), colorectal cancer (Ju T, et al. Cancer Biomark. 2014; 14(1): 63-81), pancreatic cancer (Thomas D. et al. J Cell Mol Med. 2019; 23(10): 6885-6896), and breast cancer (Cazet A. et al. Breast Cancer Res. 2010; 12(3): 204).

[0007] The development of therapeutic antibodies against Tn / STn antigens has been reported. Gatipotuzumab (formerly known as PankoMAb-GEX) has been reported to show specific binding to cancer cells with high affinity but is no longer investigated in clinical trials (Danielczyk A.et al.Cancer Immunol Immunother.2006;55(11):1337-47). Its safety was reported in a phase I study (Fiedler W.et al.Eur J Cancer.2016;63:55-63), however, when applied as a single agent as maintenance therapy for recurrent OC, gatipotuzumab showed no beneficial effect in a phase IIb study in advanced ovarian cancer (OC) (Ledermann J.et al.ESMO Open.2022 Feb;7(1):100311.Epub 2021 Dec 15). The antibody 5E5 is a murine anti-human MUC1-Tn / STn antibody that has been reported to exhibit specificity for cancer cells (Sorensen AL. et al. Glycobiology. 2006;16(2):96-107). 5E5 was used to generate a chimeric antigen receptor (CAR) that targets the TnMUC antigen. This CART-TnMUC1 construct consists of a murine anti-human scFv derived from the monoclonal antibody 5E5 that recognizes an epitope containing the Tn glycan of MUC1 and is being evaluated in clinical trials for the treatment of refractory solid tumor malignancies.

[0008] Thus, there remains a need for novel therapeutic interventions that selectively target cancer-associated MUC1. Summary of the Invention

[0009] In certain embodiments, the present disclosure provides new pharmaceutical agents for the treatment of human diseases, particularly for the treatment of cancer.

[0010] In certain embodiments, the disclosure relates to a binding domain that binds to a MUC1 peptide, wherein the MUC1 peptide comprises the amino acid sequence PAPGSTAPPAHGVTSAPDTRPAPG as set forth in SEQ ID NO:249, and the threonine (T) residue at position 14 of the MUC1 peptide comprises an α-GalNAc glycosylation or a Neu5Ac-α(2-6)-GalNAc glycosylation.

[0011] In certain embodiments, the disclosure relates to a binding domain that specifically binds to cancer-associated MUC1, where the binding domain binds to an epitope comprising a VTSA motif in the N-terminal domain of MUC1, and the threonine (T) residues are α-GalNAc glycosylated or Neu5Ac-α(2-6)-GalNAc glycosylated.

[0012] In certain embodiments, the present disclosure relates to a binding domain that has binding specificity for cancer-associated MUC1, wherein the binding domain comprises a heavy chain variable region as further defined herein.

[0013] In certain embodiments, the present disclosure relates to a binding moiety comprising two binding domains as described herein.

[0014] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising an effective amount of a binding domain or binding moiety described herein.

[0015] In certain embodiments, the disclosure relates to a binding domain, binding moiety, or pharmaceutical composition described herein for use in therapy.

[0016] In certain embodiments, the present disclosure relates to a binding domain, binding moiety, or pharmaceutical composition described herein for use in the treatment of cancer.

[0017] In certain embodiments, the present disclosure relates to a method for treating a disease, comprising administering to an individual in need of treatment an effective amount of a binding domain, binding moiety, or pharmaceutical composition described herein.

[0018] In certain embodiments, the present disclosure relates to a method for treating cancer, comprising administering to an individual in need of treatment an effective amount of a binding domain, binding moiety, or pharmaceutical composition described herein.

[0019] In certain embodiments, the present disclosure relates to a nucleic acid sequence encoding a heavy chain variable region as defined herein.

[0020] In certain embodiments, the present disclosure relates to a cell comprising a nucleic acid sequence encoding a heavy chain variable region as defined herein.

[0021] In certain embodiments, the present disclosure relates to cells that produce the binding domains or binding moieties described herein.

[0022] In certain embodiments, the present disclosure relates to a kit comprising a container comprising a binding domain or binding moiety described herein, and optionally instructions for use. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] In certain embodiments, the present disclosure provides new pharmaceutical agents for the diagnosis and treatment of disease, particularly disease in humans, particularly cancer. In certain embodiments, the present disclosure provides binding domains that specifically bind to cancer-associated MUC1 but not to MUC1 expressed on non-cancerous cells. Specifically, in certain embodiments, the present disclosure provides for the first time a genus of binding domains that specifically bind to cancer-associated MUC1 that includes Tn(α-GalNAc) glycosylation and / or STn(Neu5Ac-α(2-6)-GalNAc) glycosylation at certain amino acid residues or at certain amino acid residues of the VTSA motif that differ from normal glycosylated MUC1.

[0024] In certain embodiments, the disclosure provides a binding domain that binds to a MUC1 peptide, the MUC1 peptide having the amino acid sequence PAPGSTAPPAHGV T The peptide comprises or consists of SAPDTRPAPG (SEQ ID NO: 249), in which the threonine (T) residue at position 14 of the peptide is shown in bold and underlined herein and contains an α-GalNAc glycosylation or a Neu5Ac-α(2-6)-GalNAc glycosylation.

[0025] In certain embodiments, the disclosure provides binding domains that specifically bind to cancer-associated MUC-1, where the binding domain binds to an epitope that comprises a VTSA motif in the N-terminal domain of MUC1, and the threonine (T) residues are α-GalNAc glycosylated or Neu5Ac-α(2-6)-GalNAc glycosylated.

[0026] In certain embodiments, a binding domain of the disclosure binds to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVT*SAPDTRPAPG (SEQ ID NO: 249), where * represents Tn glycosylation. In certain embodiments, a binding domain of the disclosure binds to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVT*SAPDTRPAPG (SEQ ID NO: 249), where * represents STn glycosylation.

[0027] In certain embodiments, a binding domain of the disclosure comprises a Tn or STn glycosylation of the serine (S) residue at position 15 of a MUC1 peptide of SEQ ID NO:249 in addition to a Tn or STn glycosylation of the threonine residue at position 14 of the peptide. In certain embodiments, a binding domain of the disclosure binds to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVT*S*APDTRPAPG (SEQ ID NO:249), where * represents a Tn glycosylation. In certain embodiments, a binding domain of the disclosure binds to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVT*S*APDTRPAPG (SEQ ID NO:249), where * represents a STn glycosylation. In certain embodiments, a binding domain of the disclosure binds to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVT*S*APDTRPAPG (SEQ ID NO:249), where * represents a STn glycosylation. ● APDTRPAPG (SEQ ID NO: 249), where * represents Tn glycosylation; ● represents STn glycosylation. In certain embodiments, the binding domain of the disclosure binds to a MUC1 peptide, the MUC1 peptide having the amino acid sequence PAPGSTAPPAHGVT*S ● APDTRPAPG (SEQ ID NO: 249), where * represents STn glycosylation; ● represents Tn glycosylation.

[0028] Tn glycosylation refers to the presence of an α-GalNAc group, and STn glycosylation refers to a Neu5Ac-α(2-6)-GalNAc group.

[0029] In certain embodiments, a binding domain of the disclosure binds to human MUC1.

[0030] "Binding domain" refers to a proteinaceous molecule, or a portion of a proteinaceous molecule, that binds to a target molecule, as can be determined by binding assays well known to those skilled in the art. A binding domain can be, by way of example, a heavy chain variable region, a heavy chain variable region paired with a light chain variable region, such as an scFv, or a Fab, or a heavy chain variable region linked to a light chain variable region. In certain embodiments, a binding domain of the present disclosure is a Fab. In certain embodiments, "Fab" refers to a binding domain comprising a heavy chain variable region and a light chain variable region. In certain embodiments, "Fab" refers to a binding domain comprising a heavy chain variable region, a light chain variable region, a CH1, and a CL region.

[0031] In certain embodiments, the binding domains of the present disclosure specifically bind to cancer-associated MUC1, meaning that the binding domains do not bind detectably to MUC1 peptides lacking aberrant glycosylation patterns associated with cancer, or only at much higher concentrations as determined by glycopeptide arrays described herein, specifically glycopeptide arrays. Aberrant glycosylation patterns associated with cancer include Tn glycosylation (α-GalNAc) and STn glycosylation (Neu5Ac-α(2-6)-GalNAc). Thus, in certain embodiments of the present disclosure, the binding domains do not bind, or do not substantially bind, to MUC1 peptides comprising or consisting of the amino acid sequence set forth in SEQ ID NO:249, without α-GalNAc glycosylation or Neu5Ac-α(2-6)-GalNAc glycosylation.

[0032] In certain embodiments, the binding domain of the present disclosure binds to an epitope comprising the VTSA motif of the N-terminal domain of MUC1. In certain embodiments, the binding domain of the present disclosure does not bind, or does not substantially bind, a MUC1 peptide comprising or consisting of the amino acid sequence PAPGS*TAPPAHGVTSAPDTRPAPG (SEQ ID NO: 249), where * represents Tn or STn glycosylation. In certain embodiments, the binding domain of the present disclosure does not bind, or does not substantially bind, a MUC1 peptide comprising or consisting of the amino acid sequence PAPGS*TAPPAHGVTSAPDTRPAPG (SEQ ID NO: 249), where * represents STn glycosylation. In certain embodiments, the binding domain of the present disclosure does not bind, or does not substantially bind, a MUC1 peptide comprising or consisting of the amino acid sequence PAPGST*APPAHGVTSAPDTRPAPG (SEQ ID NO: 249), where * represents Tn or STn glycosylation. In certain embodiments, a binding domain of the disclosure binds to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGST*APPAHGVTSAPDTRPAPG (SEQ ID NO:249), where * represents Tn glycosylation. In certain embodiments, a binding domain of the disclosure does not bind to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGST*APPAHGVTSAPDTRPAPG (SEQ ID NO:249), where * represents STn glycosylation. In certain embodiments, a binding domain of the disclosure does not bind or does not substantially bind to a MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVTS*APDTRPAPG (SEQ ID NO:249), where * represents Tn or STn glycosylation. In certain embodiments, a binding domain of the disclosure does not bind, or does not substantially bind, to a MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVTS*APDTRPAPG (SEQ ID NO: 249), where * represents Tn glycosylation.In certain embodiments, a binding domain of the present disclosure does not bind or does not substantially bind to a MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVTSAPDT*RPAPG (SEQ ID NO: 249), where * represents Tn or STn glycosylation. In certain embodiments, a binding domain of the present disclosure does not bind or does not substantially bind to a MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVTSAPDT*RPAPG (SEQ ID NO: 249), where * represents Tn glycosylation. In certain embodiments, a binding domain of the present disclosure does not bind or does not substantially bind to a MUC1 peptide comprising or consisting of the amino acid sequence PAPGS*T*APPAHGVTSAPDTRPAPG (SEQ ID NO: 249), where * represents Tn or STn glycosylation. In certain embodiments, the binding domains of the disclosure also bind to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGST*APPAHGVTSAPDT*RPAPG (SEQ ID NO:249), where * represents Tn glycosylation. In certain embodiments, the binding domains of the disclosure do not bind, or do not substantially bind, to a MUC1 peptide comprising or consisting of the amino acid sequence PAPGST*APPAHGVTSAPDT*RPAPG (SEQ ID NO:249), where * represents STn glycosylation. In certain embodiments, the binding domains of the disclosure do not bind, or do not substantially bind, to a MUC1 peptide comprising or consisting of the amino acid sequence PAPGS*T*APPAHGVTSAPDT*RPAPG (SEQ ID NO:249), where * represents Tn or STn glycosylation. In certain embodiments, the binding domain of the disclosure also binds to a MUC1 peptide, the MUC1 peptide comprising or consisting of the amino acid sequence PAPGSTAPPAHGVT*SAPDT*RPAPG (SEQ ID NO: 249), where * represents Tn or STn glycosylation.

[0033] In certain embodiments, a binding domain is considered to bind a MUC1 peptide if it binds to the peptide in a bivalent monospecific IgG antibody format with a binding signal that is at least about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array. In certain embodiments, a binding domain is considered to bind a MUC1 peptide in a bivalent monospecific IgG antibody format if it binds to the peptide on a glycopeptide array with an EC50 (ug / ml) of at least about 200, or 100, or 50, or 10, or 1, or less than 0.5, or about 200-0.001, or 100-0.001, or 50-0.001, or 10-0.001, or 1-0.001, or 0.5-0.001, or 200-0.05, or 100-0.05, or 50-0.05, or 10-0.05, or 1-0.05, or 0.5-0.05. In certain embodiments, a binding domain of the present disclosure binds to a MUC1 peptide if, in a bivalent monospecific IgG antibody format, it binds to the peptide with a binding signal that is at least about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array. In certain embodiments, a binding domain is considered to bind to a MUC1 peptide if, in a bivalent monospecific IgG antibody format, it binds to the peptide on a glycopeptide array with an EC50 (ug / ml) of at least about 200, or 100, or 50, or 10, or 1, or less than 0.5, or about 200-0.001, or 100-0.001, or 50-0.001, or 10-0.001, or 1-0.001, or 0.5-0.001, or 200-0.05, or 100-0.05, or 50-0.05, or 10-0.05, or 1-0.05, or 0.5-0.05.In certain embodiments, a binding domain, in a bivalent monospecific IgG antibody format, is considered to bind a MUC1 peptide if it binds to the peptide with a binding signal that is at least about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array, and has an EC50 (ug / ml) on the glycopeptide array of at least about 200, or 100, or 50, or 10, or 1 or less than 0.5, or about 200-0.001, or 100-0.001, or 50-0.001, or 10-0.001, or 1-0.001, or 0.5-0.001, or 200-0.05, or 100-0.05, or 50-0.05, or 10-0.05, or 1-0.05, or 0.5-0.05. In certain embodiments, a binding domain of the disclosure, in a bivalent monospecific IgG antibody format, binds to a MUC1 peptide if it binds to the peptide with a binding signal that is at least about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array, and has an EC50 (ug / ml) on a glycopeptide array of at least about 200, or 100, or 50, or 10, or 1, or less than 0.5, or about 200-0.001, or 100-0.001, or 50-0.001, or 10-0.001, or 1-0.001, or 0.5-0.001, or 200-0.05, or 100-0.05, or 50-0.05, or 10-0.05, or 1-0.05, or 0.5-0.05.

[0034] In certain embodiments, a binding domain is considered to not bind or not substantially bind MUC1 peptide when it binds to the peptide in a bivalent monospecific IgG antibody format with a binding signal less than about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array. In certain embodiments, a binding domain is considered to not bind or not substantially bind MUC1 peptide when it binds to the peptide in a bivalent monospecific IgG antibody format with an EC50 (ug / ml) greater than about 200 on a glycopeptide array. In certain embodiments, a binding domain of the present disclosure is considered to not bind or not substantially bind MUC1 peptide when it binds to the peptide in a bivalent monospecific IgG antibody format with a binding signal less than 2-fold, or about 2-3-fold, or 3-fold higher than a negative isotype control on a glycopeptide array. In certain embodiments, a binding domain is considered to not bind or not substantially bind MUC1 peptide when it binds to the peptide in a bivalent monospecific IgG antibody format with an EC50 (ug / ml) greater than 200 on a glycopeptide array. In certain embodiments, a binding domain is considered to not bind or not substantially bind MUC1 peptide if it binds to the peptide in a bivalent monospecific IgG antibody format with a binding signal less than about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array. In certain embodiments, a binding domain is considered to not bind or not substantially bind MUC1 peptide if it binds to the peptide in a bivalent monospecific IgG antibody format with an EC50 (ug / ml) greater than about 200 on a glycopeptide array. In certain embodiments, a binding domain is considered to not bind or not substantially bind MUC1 peptide if it binds to the peptide in a bivalent monospecific IgG antibody format with a binding signal less than about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array and has an EC50 (ug / ml) greater than about 200 on a glycopeptide array.In certain embodiments, a binding domain is considered to not bind, or not substantially bind, to a MUC1 peptide in a bivalent monospecific IgG antibody format if it binds to the peptide with a binding signal that is less than about 2-fold, or about 2-3-fold, or about 3-fold higher than a negative isotype control on a glycopeptide array, and if it has an EC50 (ug / ml) of greater than 200 on a glycopeptide array.

[0035] For purposes of this disclosure, determining whether a binding domain binds to a MUC1 peptide is performed by using a glycopeptide array. The binding data for the binding domains provided herein is obtained by the glycopeptide array described in Example 5. Thus, in certain embodiments, the binding of the binding domains of the present disclosure described herein to a MUC1 peptide or interaction with a VTSA epitope is determined in a glycopeptide array as described in Example 5.

[0036] Briefly, glycopeptide arrays as described in Example 5 are performed using the O-glycopeptides listed in Table 2. The arrays are blocked prior to addition of MUC1 IgG and control antibodies ranging from 10 μg / ml to 0.6 ng / ml. The arrays are covered with adhesive film and shaken at room temperature. The arrays are then washed and detection antibodies are applied to the arrays. The arrays are protected from light and shaken at room temperature for 1 hour, followed by washing. The arrays are read using an Innopsys InnoScan 710 microarray scanner and suitable software.

[0037] The binding domains or binding moieties of the present disclosure bind to cancer-associated MUC1, meaning that they do not bind to normal glycosylated MUC1 on non-tumor cells. As used herein, "binding to cancer-associated MUC1" refers to the typical binding ability of a binding domain or binding site to cancer-associated MUC1 present on tumor cells or cell lines engineered to express cancer-associated MUC1. Binding of a binding domain or binding moiety to an antigen can be assessed in a variety of ways. For purposes of the present disclosure, whether a binding domain or binding moiety binds to cancer-associated MUC1 is determined by incubating the binding domain or binding moiety with cells expressing cancer-associated MUC1, e.g., MC38 huMUC1 COSMC KO cells, T47D huGalNAc cells stably expressing human MUC1-STn, and / or T47D WT cells expressing moderate levels of MUC-Tn, as described herein. Unbound binding domains or binding moieties are removed and bound binding domains or binding moieties are detected, e.g., by a labeled antibody that binds to the constant domain of the bound binding domain or binding moiety.

[0038] Antigen binding can be expressed in terms of specificity and affinity. Specificity determines which antigen or epitope thereof is specifically bound by a binding domain or binding moiety. Affinity is a measure of the strength of binding to a particular antigen or epitope.

[0039] In certain embodiments, the binding domain of the present disclosure binds to cancer-associated human MUC1.

[0040] In certain embodiments, the binding domain of the present disclosure comprises: a) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences shown in SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; b) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; c) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, respectively; d) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively; e) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively; f) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24, respectively; g) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:26, SEQ ID NO:27, and SEQ ID NO:28, respectively; h) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; i) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively; j) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively; k) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44, respectively; l) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 46, SEQ ID NO: 47, and SEQ ID NO: 48, respectively; m) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 50, SEQ ID NO: 51, and SEQ ID NO: 52, respectively; n) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56, respectively; o) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:58, SEQ ID NO:60, and SEQ ID NO:61, respectively; p) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, respectively; q) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69, respectively; r) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 71, SEQ ID NO: 72, and SEQ ID NO: 73, respectively; s) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 75, SEQ ID NO: 76, and SEQ ID NO: 77, respectively; t) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 79, SEQ ID NO: 80, and SEQ ID NO: 81, respectively; u) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 83, SEQ ID NO: 84, and SEQ ID NO: 85, respectively; v) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 87, SEQ ID NO: 88, and SEQ ID NO: 89, respectively; w) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 91, SEQ ID NO: 92, and SEQ ID NO: 93, respectively; x) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97, respectively; y) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 99, SEQ ID NO: 100, and SEQ ID NO: 101, respectively; z) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 103, SEQ ID NO: 104, and SEQ ID NO: 105, respectively; aa) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 107, SEQ ID NO: 108, and SEQ ID NO: 109, respectively; bb) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 111, SEQ ID NO: 112, and SEQ ID NO: 113, respectively; cc) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 115, SEQ ID NO: 116, and SEQ ID NO: 117, respectively; dd) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 119, SEQ ID NO: 120, and SEQ ID NO: 121, respectively; ee) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 123, SEQ ID NO: 124, and SEQ ID NO: 125, respectively; ff) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 127, SEQ ID NO: 128, and SEQ ID NO: 129, respectively; gg) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 131, SEQ ID NO: 132, and SEQ ID NO: 133, respectively; hh) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 135, SEQ ID NO: 136, and SEQ ID NO: 137, respectively; ii) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 139, SEQ ID NO: 140, and SEQ ID NO: 141, respectively; jj) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 143, SEQ ID NO: 144, and SEQ ID NO: 145, respectively; kk) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 147, SEQ ID NO: 148, and SEQ ID NO: 149, respectively; ll) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 151, SEQ ID NO: 152, and SEQ ID NO: 153, respectively; mm) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 155, SEQ ID NO: 156, and SEQ ID NO: 157, respectively; nn) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 159, SEQ ID NO: 160, and SEQ ID NO: 161, respectively; oo) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 163, SEQ ID NO: 164, and SEQ ID NO: 165, respectively; pp) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 167, SEQ ID NO: 168, and SEQ ID NO: 169, respectively; qq) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 171, SEQ ID NO: 172, and SEQ ID NO: 173, respectively; rr) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 175, SEQ ID NO: 176, and SEQ ID NO: 177, respectively; ss) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 179, SEQ ID NO: 180, and SEQ ID NO: 181, respectively; tt) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 183, SEQ ID NO: 184, and SEQ ID NO: 185, respectively; uu) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 187, SEQ ID NO: 188, and SEQ ID NO: 189, respectively; vv) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 191, SEQ ID NO: 192, and SEQ ID NO: 193, respectively; ww) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences shown in SEQ ID NO: 195, SEQ ID NO: 196, and SEQ ID NO: 197, respectively; xx) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 199, SEQ ID NO: 200, and SEQ ID NO: 201, respectively; yy) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 203, SEQ ID NO: 204, and SEQ ID NO: 205, respectively; or zz) a heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 207, SEQ ID NO: 208, and SEQ ID NO: 209, respectively.

[0041] The heavy chain variable region of the MUC1-binding domain of the disclosure may include a limited number of non-conservative amino acid substitutions, such as 1, 2, or 3, or an unlimited number of conservative amino acid substitutions.

[0042] In certain embodiments, the MUC1 binding domain of the present disclosure also includes MUC1 binding domain variants, in which each of the HCDRs may contain up to three, two, or one amino acid variations, e.g., substitutions. In certain embodiments, only one or two HCDRs may contain up to three, two, or one amino acid variations, e.g., substitutions. In certain embodiments, such variants do not contain amino acid variations in HCDR3. In certain embodiments, the amino acid variations are conservative amino acid substitutions.

[0043] Typically, conservative amino acid substitution involves variation of an amino acid with a homologous amino acid residue, which is a residue that shares similar characteristics or properties. Homologous amino acids are known in the art, as are routine methods known for making amino acid substitutions within an antibody binding domain without significantly affecting antibody binding or function, see, for example, Lehninger's principles of biochemistry (Nelson DL, Cox MM and Lehninger AL. New York: WH Freeman, 2017) or Handbook of Biochemistry (Berg JM, Tymoczko JL and Stryer L. New York: WH Freeman, 2007), which are incorporated herein in their entirety. When determining whether an amino acid can be replaced with a conservative amino acid, an evaluation can typically be made from factors such as, but not limited to, (a) the structure of the polypeptide backbone in the replacement region, e.g., sheet or helix structure, (b) the charge or hydrophobicity of the molecule at the target site, and / or (c) the bulk of the side chain. If a residue can be replaced with a residue that has a common feature, such as a similar side chain or similar charge or hydrophobicity, such a residue is preferred as a replacement. For example, the following groups can be determined: (1) non-polar: Ala (A), Gly (G), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M), (2) uncharged polar: Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q), (3) acidic: Asp (D), Glu (E), and (4) basic: Lys (K), Arg (R), His (H). Alternatively, amino acids may be grouped as follows: (1) aromatic: Phe(F), Trp(W), Tyr(Y), (2) nonpolar: Leu(L), Val(V), Ile(I), Ala(A), Met(M), (3) aliphatic: Ala(A), Val(V), Leu(L), Ile(I), (4) acidic: Asp(D), Glu(E), (5) basic: His(H), Lys(K), Arg(R), and (6) polar: Gln(Q), Asn(N), Ser(S), Thr(T), Tyr(Y). Alternatively, amino acid residues may be divided into groups based on common side chain properties.(1) Hydrophobic: Met(M), Ala(A), Val(V), Leu(L), Ile(I), (2) Neutral hydrophilic: Cys(C), Ser(S), Thr(T), Asn(N), Gln(Q), (3) Acidic: Asp(D), Glu(E), (4) Basic: His(H), Lys(K), Arg R), (5) residues that influence chain orientation: Gly (G), Pro (P), and (6) aromatic: Trp (W), Tyr (Y), Phe (F).

[0044] Substitution with another amino acid residue in the same group is preferred. Thus, conservative amino acid substitutions may involve replacing a member of one of these classes with another member of the same class. Typically, the variation does not result in loss or substantial loss of the binding specificity of the binding domain for its intended target.

[0045] Additional types of amino acid variations include variations resulting from somatic hypermutation and / or affinity maturation. Binding variants encompassed by the present disclosure include somatic hypermutation or affinity maturation heavy chain variable regions that are heavy chain variable regions derived from the same VH gene segment as the heavy chain variable regions described herein by sequence, and the variants have amino acid variations, including non-conservative and / or conservative amino acid substitutions in one, two, or all three HCDRs. Routine methods for affinity maturation of antibody binding domains are widely known in the art, see, for example, Taba sinezhad M. et al. Immunol Lett. 2019;212:106-113.

[0046] Whether amino acid residues in the CDR and / or framework regions can be substituted, for example, with conservative amino acid residues and without or substantially without loss of binding specificity can be determined by methods well known in the art. Exemplary experiments include, but are not limited to, alanine scanning (Cunningham BC, Wells JA. Science. 1989; 244(4908): 1081-5) and deep mutation scanning (Araya CL, Fowler DM. Trends Biotechnol. 2011; 29(9): 435-42). Computational methods have also been developed that can predict the effects of amino acid mutations, for example as described in Sruthi CK, Prakash M. PLoS One. 2020; 15(1): e0227621, Choi Y. et al. PLoS One. 2012; 7(10): e46688, and Munro D, Singh M. Bioinformatics. 2020; 36(22-23): 5322-9.

[0047] In certain embodiments, the MUC1 binding domains of the disclosure also include MUC1 binding domain variants that contain one or more variations in the framework regions, in addition to the variations in the HCDRs described above. In certain embodiments, a MUC1-binding domain of the disclosure comprises a heavy chain variable region having an amino acid sequence set forth in any one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, or having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto. In certain embodiments, MUC1-binding domain variants of the disclosure do not contain variations in the CDR regions, but contain one or more variations in the framework regions. Such variants have at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the sequences disclosed herein and are expected to retain MUC1-binding specificity. Thus, in certain embodiments, MUC1-binding domains of the disclosure include: - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 2, an HCDR2 amino acid sequence set forth in SEQ ID NO: 3, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 4; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:5, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO:6, an HCDR2 amino acid sequence set forth in SEQ ID NO:7, and an HCDR3 amino acid sequence set forth in SEQ ID NO:8; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 10, an HCDR2 amino acid sequence set forth in SEQ ID NO: 11, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 12; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 13, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 14, an HCDR2 amino acid sequence set forth in SEQ ID NO: 15, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 16; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 18, an HCDR2 amino acid sequence set forth in SEQ ID NO: 19, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 20; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 21, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 22, an HCDR2 amino acid sequence set forth in SEQ ID NO: 23, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 24; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 25, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 26, an HCDR2 amino acid sequence set forth in SEQ ID NO: 27, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 28; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 29, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 30, an HCDR2 amino acid sequence set forth in SEQ ID NO: 31, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 32; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 33, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 34, an HCDR2 amino acid sequence set forth in SEQ ID NO: 35, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 36; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 38, an HCDR2 amino acid sequence set forth in SEQ ID NO: 39, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 40; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 42, an HCDR2 amino acid sequence set forth in SEQ ID NO: 43, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 44; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 45, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 46, an HCDR2 amino acid sequence set forth in SEQ ID NO: 47, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 48; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 49, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 50, an HCDR2 amino acid sequence set forth in SEQ ID NO: 51, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 52; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 53, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 54, an HCDR2 amino acid sequence set forth in SEQ ID NO: 55, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 56; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 58, an HCDR2 amino acid sequence set forth in SEQ ID NO: 60, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 61; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 62, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 63, an HCDR2 amino acid sequence set forth in SEQ ID NO: 64, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 65; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 66, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 67, an HCDR2 amino acid sequence set forth in SEQ ID NO: 68, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 69; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 70, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 71, an HCDR2 amino acid sequence set forth in SEQ ID NO: 72, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 73; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 74, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 75, an HCDR2 amino acid sequence set forth in SEQ ID NO: 76, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 77; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 78, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 79, an HCDR2 amino acid sequence set forth in SEQ ID NO: 80, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 81; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 82, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 83, an HCDR2 amino acid sequence set forth in SEQ ID NO: 84, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 85; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 86, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 87, an HCDR2 amino acid sequence set forth in SEQ ID NO: 88, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 89; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 90, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 91, an HCDR2 amino acid sequence set forth in SEQ ID NO: 92, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 93; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 94, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 95, an HCDR2 amino acid sequence set forth in SEQ ID NO: 96, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 97; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 99, an HCDR2 amino acid sequence set forth in SEQ ID NO: 100, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 101; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 102, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 103, an HCDR2 amino acid sequence set forth in SEQ ID NO: 104, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 105; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 106, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 107, an HCDR2 amino acid sequence set forth in SEQ ID NO: 108, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 109; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 110, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 111, an HCDR2 amino acid sequence set forth in SEQ ID NO: 112, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 113; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 114, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 115, an HCDR2 amino acid sequence set forth in SEQ ID NO: 116, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 117; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 118, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 119, an HCDR2 amino acid sequence set forth in SEQ ID NO: 120, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 121; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 122, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 123, an HCDR2 amino acid sequence set forth in SEQ ID NO: 124, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 125; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 126, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 127, an HCDR2 amino acid sequence set forth in SEQ ID NO: 128, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 129; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 131, an HCDR2 amino acid sequence set forth in SEQ ID NO: 132, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 133; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 134, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 135, an HCDR2 amino acid sequence set forth in SEQ ID NO: 136, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 137; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 138, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 139, an HCDR2 amino acid sequence set forth in SEQ ID NO: 140, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 141; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 142, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 143, an HCDR2 amino acid sequence set forth in SEQ ID NO: 144, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 145; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 146, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 147, an HCDR2 amino acid sequence set forth in SEQ ID NO: 148, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 149; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 150, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 151, an HCDR2 amino acid sequence set forth in SEQ ID NO: 152, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 153; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 154, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 155, an HCDR2 amino acid sequence set forth in SEQ ID NO: 156, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 157; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 158, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 159, an HCDR2 amino acid sequence set forth in SEQ ID NO: 160, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 161; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 162, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 163, an HCDR2 amino acid sequence set forth in SEQ ID NO: 164, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 165; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 166, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 167, an HCDR2 amino acid sequence set forth in SEQ ID NO: 168, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 169; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 170, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 171, an HCDR2 amino acid sequence set forth in SEQ ID NO: 172, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 173; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 174, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 175, an HCDR2 amino acid sequence set forth in SEQ ID NO: 176, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 177; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 178, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 179, an HCDR2 amino acid sequence set forth in SEQ ID NO: 180, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 181; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 182, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 183, an HCDR2 amino acid sequence set forth in SEQ ID NO: 184, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 185; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 186, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 187, an HCDR2 amino acid sequence set forth in SEQ ID NO: 188, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 189; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 190, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 191, an HCDR2 amino acid sequence set forth in SEQ ID NO: 192, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 193; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 194, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 195, an HCDR2 amino acid sequence set forth in SEQ ID NO: 196, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 197; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 198, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 199, an HCDR2 amino acid sequence set forth in SEQ ID NO: 200, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 201; - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 202, comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 203, an HCDR2 amino acid sequence set forth in SEQ ID NO: 204, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 205; or - a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 206, and comprising an HCDR1 amino acid sequence set forth in SEQ ID NO: 207, an HCDR2 amino acid sequence set forth in SEQ ID NO: 208, and an HCDR3 amino acid sequence set forth in SEQ ID NO: 209.

[0048] The MUC1 binding domains of the present disclosure are generated using a common light chain, in particular a common light chain designated VK1-39 / JK1. The binding domains of the present disclosure can include any suitable light chain, including but not limited to common light chains known in the art. In certain embodiments, the MUC1 binding domains of the present disclosure include the common light chain VK1-39 / JK1, or a variant thereof having a limited number, for example, one, two, or three non-conservative amino acid substitutions, or an unlimited number of conservative amino acid substitutions.

[0049] In certain embodiments, a MUC1-binding domain of the present disclosure comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:218, or a variant thereof. In certain embodiments, a MUC1-binding domain of the present disclosure comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:218, or having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto.

[0050] In certain embodiments, a MUC1-binding domain of the disclosure comprises a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) having the amino acid sequences set forth in SEQ ID NO:219, SEQ ID NO:220, and SEQ ID NO:221, respectively. In certain embodiments, the light chain variable region of a MUC1-binding domain of the disclosure, including variants thereof, each of the LCDRs can comprise up to three, two, or one amino acid substitutions. The amino acid substitutions are, by way of example, conservative amino acid substitutions.

[0051] In certain embodiments, the MUC1-binding domain of the present disclosure also includes MUC1-binding domain variants that, in addition to the variations in the LCDRs described above, contain one or more variations in the framework regions. In certain embodiments, the MUC1-binding domain variants of the present disclosure do not contain variations in the LCDR regions, but contain one or more variations in the framework regions. Such variants have at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the sequences disclosed herein. Thus, in certain embodiments, the MUC1-binding domain of the present disclosure includes - a light chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 218, and comprising an LCDR1 amino acid sequence set forth in SEQ ID NO: 219, an LCDR2 amino acid sequence set forth in SEQ ID NO: 220, and an LCDR3 amino acid sequence set forth in SEQ ID NO: 221.

[0052] The light chain or light chain variable region comprising these LCDRs and / or light chain variable regions may be a light chain referred to in the art as VK1-39 / JK1. This is a common light chain. The term "common light chain" according to the present disclosure refers to a light chain that can be paired with multiple different heavy chains, such as heavy chains with different antigen or epitope binding specificities, for example. The term "common light chain" encompasses light chains that are identical or have some amino acid sequence differences, while the binding specificity of the full-length antibody is not affected. For example, it is possible within the definition of common light chain used herein to prepare or find light chains that are not identical but are still functionally equivalent by using well-established variations that introduce conservative amino acid changes, amino acid changes in regions known to not contribute or only partially contribute to binding specificity when paired with a heavy chain, for example.

[0053] Apart from the common light chains comprising the LCDRs and / or light chain variable regions described above, other common light chains known in the art may be used. Examples of such common light chains include, but are not limited to, VK1-39 / JK5, ​​which comprises a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 229. In certain embodiments, the light chain comprises a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 229, each of the LCDRs may comprise up to three, two, or one amino acid variations, e.g., substitutions. In certain embodiments, the light chain comprises a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 229 or having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto. In certain embodiments, the light chain comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) having the amino acid sequences set forth in SEQ ID NO: 230, SEQ ID NO: 231, and SEQ ID NO: 232, respectively, and VK3-15 / JK1 comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 234. In certain embodiments, the light chain comprises a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 234, and each of the LCDRs may comprise up to three, two, or one amino acid variations, e.g., substitutions. In certain embodiments, the light chain comprises a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 234, or having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto.In certain embodiments, the light chain comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) having the amino acid sequences set forth in SEQ ID NO: 235, SEQ ID NO: 236, and SEQ ID NO: 237, respectively, and VK3-20 / JK1 comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 239. In certain embodiments, the light chain comprises a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 239, and each of the LCDRs may comprise up to three, two, or one amino acid variations, e.g., substitutions. In certain embodiments, the light chain comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 239, or at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto. In certain embodiments, the light chain comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) having the amino acid sequences set forth in SEQ ID NO: 240, SEQ ID NO: 241, and SEQ ID NO: 242, respectively, and VL3-21 / JL3 comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 244. In certain embodiments, the light chain comprises a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 244, where each of the LCDRs may contain up to three, two, or one amino acid variation, e.g., substitution. In certain embodiments, the light chain comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 244, or having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto.In certain embodiments, the light chain comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) having the amino acid sequences set forth in SEQ ID NO: 245, SEQ ID NO: 246, and SEQ ID NO: 247, respectively.

[0054] VK1-39 is an abbreviation for Immunoglobulin variable kappa 1-39 gene. This gene is also known as Immunoglobulin kappa variable 1-39, IGKV139, IGKV1-39, IgVκ1-39. The external Ids of this gene are HGNC:5740; Entrez Gene:28930; Ensembl:ENSG00000242371. The amino acid sequence for VK1-39 is given as SEQ ID NO:227. This is the sequence of the V region. The V region can be combined with one of five J regions. Preferred VJ region sequences are designated as VK1-39 / JK1 (SEQ ID NO:228) and VK1-39 / JK5 (SEQ ID NO:229), with alternative names IgVκ1-39*01 / IGJκ1*01 or IgVκ1-39*01 / IGJκ5*01 (names given by the IMGT database at imgt.org). These names are exemplary and encompass allelic variants of the gene segments.

[0055] VK3-15 is an abbreviation for Immunoglobulin variable kappa 3-15 gene. This gene is also known as Immunoglobulin kappa variable 3-15, IGKV315, IGKV3-15, IgVκ3-15. The external Id of this gene is HGNC:5816; Entrez Gene:28913; Ensembl:ENSG00000244437. The amino acid sequence for VK3-15 is given as SEQ ID NO:233. This is the sequence of the V region. The V region can be combined with one of five J regions. A suitable VJ region sequence is shown as VK3-15 / JK1 (SEQ ID NO:234), with alternative names Vκ3-15*01 / IGJκ1*01 (named by the IMGT database world wide web at imgt.org). This name is exemplary and encompasses allelic variants of the gene segment.

[0056] VK3-20 is an abbreviation for Immunoglobulin variable kappa 3-20 gene. This gene is also known as Immunoglobulin kappa variable 3-20, IGKV320, IGKV3-20, IgVκ3-20. The external Id of this gene is HGNC:5817; Entrez Gene:28912; Ensembl:ENSG00000239951. The amino acid sequence for VK3-20 is as in SEQ ID NO:238. This is the sequence of the V region. The V region can be combined with one of five J regions. A suitable VJ region sequence is shown as VK3-20 / JK1 (SEQ ID NO:239), with alternative names being IgVκ3-20*01 / IGJκ1*01 (named by the IMGT database world wide web at imgt.org). This name is exemplary and encompasses allelic variants of the gene segment.

[0057] VL3-21 is an abbreviation for Immunoglobulin variable lambda 3-21 gene. This gene is also known as Immunoglobulin lambda variable 3-21, IGLV321, IGLV3-21, IgVlambda3-21. The external Id of this gene is HGNC:5905; Entrez Gene:28796; Ensembl:ENSG00000211662.2. The amino acid sequence for VL3-21 is given as SEQ ID NO:243. This is the sequence of the V region. The V region can be combined with one of five J regions. A suitable VJ region sequence is shown as VL3-21 / JL3 (SEQ ID NO:244), with an alternative name being IgVlambda3-21 / IGJlambda3 (named by the IMGT database World Wide Web at imgt.org). This name is exemplary and encompasses allelic variants of the gene segment.

[0058] Furthermore, any light chain variable region of a MUC1 antibody available in the art, or, for example, any other light chain variable region that can be readily obtained from an antibody display library by exhibiting antigen-binding activity when paired with the MUC1-binding domain of the present disclosure, may be used.

[0059] In certain embodiments, the MUC1 binding domain of the binding moiety of the present disclosure may further comprise a CH1 and a CL region. Any CH1 domain, particularly a human CH1 domain, may be used. An example of a suitable CH1 domain is provided by the amino acid sequence provided as SEQ ID NO: 223. Any CL domain, particularly a human CL, may be used. An example of a suitable CL domain is provided by the amino acid sequence provided as SEQ ID NO: 226.

[0060] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences shown in SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0061] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0062] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0063] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0064] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0065] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0066] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0067] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0068] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0069] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0070] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 42, SEQ ID NO: 43 and SEQ ID NO: 44, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0071] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 46, SEQ ID NO: 47 and SEQ ID NO: 48, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0072] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as shown in SEQ ID NO: 50, SEQ ID NO: 51 and SEQ ID NO: 52, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0073] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 54, SEQ ID NO: 55 and SEQ ID NO: 56, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0074] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 58, SEQ ID NO: 60 and SEQ ID NO: 61, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0075] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 63, SEQ ID NO: 64 and SEQ ID NO: 65, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0076] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 67, SEQ ID NO: 68 and SEQ ID NO: 69, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0077] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 71, SEQ ID NO: 72 and SEQ ID NO: 73, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0078] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 75, SEQ ID NO: 76 and SEQ ID NO: 77, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0079] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 79, SEQ ID NO: 80 and SEQ ID NO: 81, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0080] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 83, SEQ ID NO: 84 and SEQ ID NO: 85, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0081] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 87, SEQ ID NO: 88 and SEQ ID NO: 89, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0082] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 91, SEQ ID NO: 92 and SEQ ID NO: 93, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0083] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 95, SEQ ID NO: 96 and SEQ ID NO: 97, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0084] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 99, SEQ ID NO: 100 and SEQ ID NO: 101, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0085] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 103, SEQ ID NO: 104 and SEQ ID NO: 105, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0086] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 107, SEQ ID NO: 108 and SEQ ID NO: 109, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0087] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 111, SEQ ID NO: 112 and SEQ ID NO: 113, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0088] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 115, SEQ ID NO: 116 and SEQ ID NO: 117, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0089] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 119, SEQ ID NO: 120 and SEQ ID NO: 121, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0090] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 123, SEQ ID NO: 124 and SEQ ID NO: 125, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0091] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 127, SEQ ID NO: 128 and SEQ ID NO: 129, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0092] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 131, SEQ ID NO: 132 and SEQ ID NO: 133, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0093] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 135, SEQ ID NO: 136 and SEQ ID NO: 137, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0094] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 139, SEQ ID NO: 140 and SEQ ID NO: 141, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0095] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0096] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 147, SEQ ID NO: 148 and SEQ ID NO: 149, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0097] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 151, SEQ ID NO: 152 and SEQ ID NO: 153, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0098] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 155, SEQ ID NO: 156 and SEQ ID NO: 157, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0099] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 159, SEQ ID NO: 160 and SEQ ID NO: 161, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0100] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 163, SEQ ID NO: 164 and SEQ ID NO: 165, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0101] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 167, SEQ ID NO: 168 and SEQ ID NO: 169, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0102] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 171, SEQ ID NO: 172 and SEQ ID NO: 173, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0103] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 175, SEQ ID NO: 176 and SEQ ID NO: 177, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0104] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 179, SEQ ID NO: 180 and SEQ ID NO: 181, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0105] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 183, SEQ ID NO: 184 and SEQ ID NO: 185, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0106] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 187, SEQ ID NO: 188 and SEQ ID NO: 189, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0107] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 191, SEQ ID NO: 192 and SEQ ID NO: 193, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0108] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 195, SEQ ID NO: 196 and SEQ ID NO: 197, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0109] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 199, SEQ ID NO: 200 and SEQ ID NO: 201, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0110] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 203, SEQ ID NO: 204 and SEQ ID NO: 205, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0111] In one embodiment, the present disclosure provides: - a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2) and a heavy chain CDR3 (HCDR3) having the amino acid sequences as set forth in SEQ ID NO: 207, SEQ ID NO: 208 and SEQ ID NO: 209, respectively; a light chain CDR1 (LCDR1) having the amino acid sequence set forth in SEQ ID NO: 219, a light chain CDR2 (LCDR2) having the amino acid sequence set forth in SEQ ID NO: 220, and a light chain CDR3 (LCDR3) having the amino acid sequence set forth in SEQ ID NO: 221; Each of the HCDRs and / or LCDRs may contain up to 3, 2, or 1 amino acid variations, e.g., substitutions. In certain embodiments, the HCDRs and / or LCDRs do not contain any amino acid variations.

[0112] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:1, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0113] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:5, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0114] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 9, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0115] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0116] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 17, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0117] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 21, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0118] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 25, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0119] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 29, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0120] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 33, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0121] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 37, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0122] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 41, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0123] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 45, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0124] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 49, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0125] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 53, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0126] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 57, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0127] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 62, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0128] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 66, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0129] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 70, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0130] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 74, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0131] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 78, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0132] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 82, or a heavy chain variable region having at least 80%, or at least 85%, at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0133] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 86, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0134] In one embodiment, the present disclosure provides: - a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 90, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0135] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 94, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0136] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 98, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0137] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 102, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0138] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 106, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0139] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 110, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0140] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 114, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0141] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 118, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0142] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 122, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0143] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 126, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0144] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 130, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0145] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 134, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0146] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 138, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0147] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 142, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0148] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 146, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0149] In one embodiment, the present disclosure provides: - a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 150, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0150] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 154, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0151] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 158, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0152] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 162, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0153] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 166, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0154] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 170, or a heavy chain variable region having at least 80%, or at least 85%, at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0155] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 174, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0156] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 178, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0157] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 182, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0158] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 186, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0159] In one embodiment, the present disclosure provides: - a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 190, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0160] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 194, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0161] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 198, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0162] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 202, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0163] In one embodiment, the present disclosure provides: - a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 206, or a heavy chain variable region having at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identity thereto; - a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 218, or a light chain variable region that is at least 80%, or at least 85%, or at least 90%, or at least 95% sequence identical thereto. In certain embodiments, each of the heavy chain variable region and the light chain variable region comprises an HCDR and an LCDR, respectively, that do not contain an amino acid variation. In certain embodiments, each of the heavy chain variable region and the light chain variable region does not contain an amino acid variation.

[0164] "Percent identity" in the present specification with respect to a nucleic acid or amino acid sequence is defined as the percentage of residues in a candidate sequence that are identical to the residues in a selected sequence after aligning the sequences for optimal comparison purposes. Gaps can be introduced in either of the two sequences being compared to optimize the alignment between the two sequences. Such alignment can be performed over the entire length of the sequences being compared. Alternatively, alignment can be performed over a shorter length, for example, about 20, about 50, about 100 or more nucleic acids / bases or amino acids. Sequence identity is the percentage of perfect matches between the two sequences over the reported aligned region.

[0165] Comparison of sequences and determination of the percentage of sequence identity between two sequences can be achieved using a mathematical algorithm. Those skilled in the art will recognize the fact that several different computer programs are available for aligning two sequences and determining the identity between two sequences (Kruskal JB. SIAM Review. 1983; 25(2), 201-237). The percentage of sequence identity between two amino acid or nucleic acid sequences can be determined using the Needleman-Wunsch algorithm for aligning two sequences. (Needleman SB, Wunsch CD. J Mol Biol. 1970; 48(3): 443-53). The Needleman-Wunsch algorithm is implemented in the computer program NEEDLE. For the purposes of the present invention, the percent identity of amino acid and nucleic acid sequences is determined using the NEEDLE program from the EMBOSS package (version 2.8.0, Rice P. et al. Trends Genet. 2000; 16(6):276-7, http: / / emboss.bioinformatics.nl / ). For protein sequences, EBLOSUM62 is used as the substitution matrix. For DNA sequences, DNAFULL is used. The parameters used are gap open penalty 10 and gap extension penalty 0.5.

[0166] After alignment with the program NEEDLE as described above, the percentage of sequence identity between a query sequence and a sequence of the invention is calculated as follows: the number of corresponding positions in the alignment represents the number of identical amino acids or identical nucleotides in both sequences divided by the total length of the alignment after subtraction of the total number of gaps in the alignment.

[0167] In certain embodiments, the present disclosure also provides binding moieties comprising a MUC1 binding domain as described herein. In certain embodiments, the binding moieties of the present disclosure comprise two MUC1 binding domains as described herein. In certain embodiments, the binding moieties of the present disclosure consist of two MUC1 binding domains and an Fc region. In certain embodiments, the Fc region comprises a hinge, a CH2, and a CH3 domain.

[0168] "Binding moiety" refers to a proteinaceous molecule that comprises a binding domain, examples of which include, for example, full-length IgG antibodies, immunoconjugates, diabodies, BiTEs, Fab fragments, scFvs, tandem scFvs, single domain antibodies (V HH and V H These include all antibody formats available in the art, such as scFv, minibodies, scFab, scFv-zippers, nanobodies, DART molecules, TandAbs, Fab-scFv, F(ab)'2, F(ab)'2-scFv2, and intrabodies.

[0169] In certain embodiments, the binding moiety of the present disclosure is a monospecific binding moiety, particularly a monospecific antibody. A monospecific antibody according to the present disclosure is an antibody that comprises one or more binding domains with specificity for a single target, in any antibody format. In certain embodiments, the monospecific binding moiety of the present disclosure may further comprise an Fc region or a portion thereof. In certain embodiments, the monospecific binding moiety of the present disclosure is an IgG1 antibody.

[0170] The Fc region mediates antibody effector functions such as complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP). Depending on the application of the therapeutic antibody or Fc fusion protein, it may be desirable to reduce or increase effector functions.

[0171] In certain embodiments, the binding moieties of the present disclosure have Fc effector function. In certain embodiments, the binding moieties of the present disclosure have enhanced Fc effector function. In certain embodiments, the binding moieties of the present disclosure exhibit antibody-dependent cell-mediated cytotoxicity (ADCC). Binding moieties such as antibodies can be engineered to improve ADCC activity (for review, see Kubota T et al. Cancer Sci. 2009; 100(9): 1566-72). As an example, if the antibody itself has low ADCC activity, the ADCC activity of the antibody can be improved by slightly modifying the constant region of the antibody (Junttila TT. et al. Cancer Res. 2010; 70(11): 4481-9). Changes may also be made to improve storage or production, or to remove C-terminal lysines (Kubota T et al. Cancer Sci. 2009; 100(9): 1566-72). Another way to improve the ADCC activity of antibodies is by enzymatically interfering with the glycosylation pathway resulting in reduced fucose (von Horsten HH.et al.Glycobiology.2010;20(12):1607-18). Alternatively or additionally, multiple other strategies can be used to achieve enhanced ADCC, including, for example, glycoengineering (Kyowa Hakko / Biowa, GlycArt(Roche)and Eureka Therapeutics) and mutagenesis, all of which aim to improve Fc binding to the low affinity activating FcγRIIIa and / or reduce binding to the low affinity inhibitory FcγRIIb. In certain embodiments, the binding moieties of the present disclosure exhibit enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). In certain embodiments, the binding moieties of the present disclosure are afucosylated.

[0172] In certain embodiments, the binding moieties of the present disclosure have a higher binding signal than a reference antibody. In certain embodiments, the binding signal is as measured by FACS assay using MUC1-Tn-expressing cells or MUC-1-STn-expressing cells. In certain embodiments, the MUC1-Tn-expressing cells are MCF7 or T47D cells as described herein. In certain embodiments, the MUC1-Tn-expressing cells are huMUC1 COSMC KO cells, which can be generated by stably transfecting MC38 cells with human MUC1 and knocking out the C1galt1c1 (COSMC) gene, as described herein. In certain embodiments, the MUC1-STn-expressing cells are T47D huGalNAc cells, which can be generated by stably transfecting T47D cells with a plasmid encoding ST6GALNAC, as described herein. In certain embodiments, the reference antibody is a bivalent monospecific antibody comprising two heavy chains having the amino acid sequence set forth in SEQ ID NO: 210 and two light chains having the amino acid sequence set forth in SEQ ID NO: 211.

[0173] In certain embodiments, the disclosure provides a binding moiety comprising a MUC1-binding domain of the disclosure, the binding moiety comprising: an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO:5 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO:218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 9 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 13 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 17 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 21 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 25 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 29 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 33 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 37 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 41 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 45 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 49 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 53 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 57 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 62 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 66 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 70 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 74 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 78 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 82 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 86 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 90 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 94 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 98 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 102 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 106 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 110 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 114 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 118 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 122 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 126 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 130 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 134 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 138 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 142 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 146 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 150 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 154 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 158 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 162 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 166 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 170 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 174 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 178 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 182 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 186 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 190 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 194 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 198 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 202 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218, and - an antibody comprising two heavy chain variable regions having the amino acid sequence as set forth in SEQ ID NO: 206 and a light chain variable region having the amino acid sequence as set forth in SEQ ID NO: 218; or a binding moiety that competes with the antibody for binding to a MUC1 peptide comprising the amino acid sequence PAPGSTAPPAHGVT*SAPDTRPAPG (SEQ ID NO: 249), and / or PAPGSTAPPAHGVT*S*APDTRPAPG (SEQ ID NO: 249), where * represents Tn or STn glycosylation.

[0174] Further provided herein are nucleic acids useful for producing the MUC1-binding domain of the present disclosure, or binding moieties comprising the MUC1-binding domain. In certain embodiments, such nucleic acids comprise a nucleic acid sequence encoding a heavy chain variable region of the MUC1-binding domain described herein. In certain embodiments, the nucleic acids of the present disclosure may further comprise a nucleic acid sequence encoding a CH1 region, and optionally a hinge, a CH2, and / or a CH3 region. In certain embodiments, the nucleic acids of the present disclosure may further comprise at least one nucleic acid sequence encoding a light chain variable region, and optionally a CL region. In certain embodiments, the light chain variable region may be a common light chain variable region described herein.

[0175] Further provided herein is a vector useful for producing the MUC1 binding domain of the present disclosure, or a binding moiety comprising the MUC1 binding domain. In certain embodiments, such an expression vector comprises a nucleic acid sequence encoding a heavy chain variable region of the MUC1 binding domain described herein. In certain embodiments, the vector of the present disclosure may further comprise a nucleic acid sequence encoding a CH1 region, and optionally a hinge, CH2, and / or CH3 region. In certain embodiments, the vector of the present disclosure may further comprise at least one nucleic acid sequence encoding a light chain variable region, and optionally a CL region. In certain embodiments, the light chain variable region may be a common light chain variable region described herein.

[0176] In certain embodiments, the present disclosure also provides a cell comprising a nucleic acid sequence encoding a heavy chain variable region of a MUC1 binding domain described herein. In certain embodiments, the cell of the present disclosure may further comprise a nucleic acid sequence encoding a CH1 region, and optionally a hinge, CH2, and / or CH3 region. In certain embodiments, the cell of the present disclosure may further comprise at least one nucleic acid sequence encoding a light chain variable region, and optionally a CL region. In certain embodiments, the light chain variable region may be a common light chain variable region described herein.

[0177] In certain embodiments, the present disclosure also provides cells that produce the MUC1 binding domain described herein, or a binding moiety that includes the MUC1 binding domain. In certain embodiments, such cells can be recombinant cells that have been transformed with a vector of the present disclosure. In certain embodiments, the cells of the present disclosure comprise a nucleic acid sequence that encodes a heavy chain variable region of a MUC1 binding domain described herein. In certain embodiments, the cells of the present disclosure further comprise a nucleic acid sequence that encodes a CH1 region, and optionally a hinge, CH2, and / or CH3 region. In certain embodiments, the cells of the present disclosure further comprise at least one nucleic acid sequence that encodes a light chain variable region, particularly a light chain variable region described herein, and optionally a CL region.

[0178] In certain embodiments, the disclosure provides a pharmaceutical composition comprising an effective amount of a MUC1 binding domain, or a binding moiety comprising a MUC1 binding domain, described herein, and optionally a pharma- ceutically acceptable carrier.

[0179] In certain embodiments, the disclosure provides a MUC1 binding domain as described herein, or a binding moiety comprising a MUC1 binding domain as described herein, and a pharmaceutical composition as described herein, for use in therapy.

[0180] In certain embodiments, the disclosure provides a MUC1-binding domain described herein, or a binding moiety comprising a MUC1-binding domain, or a pharmaceutical composition described herein, for use in the treatment of cancer.

[0181] In certain embodiments, the disclosure provides methods for treating a disease, comprising administering to an individual in need of treatment an effective amount of a MUC1-binding domain, or a binding moiety comprising a MUC1-binding domain, as described herein, or a pharmaceutical composition as described herein.

[0182] In certain embodiments, the disclosure provides methods for treating cancer, comprising administering to an individual in need of treatment an effective amount of a MUC1-binding domain, or a binding moiety comprising a MUC1-binding domain, as described herein, or a pharmaceutical composition as described herein.

[0183] As used herein, the terms "individual," "subject," and "patient" are used interchangeably and refer to mammals such as humans, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, monkeys, cows, horses, pigs, etc., particularly humans with cancer.

[0184] As used herein, the terms "treat", "treating" and "treatment" refer to any type of intervention or process performed on a subject or administering to a subject an active agent or combination of active agents for the purpose of curing or ameliorating a disease or condition in the subject or for the purpose of producing a positive therapeutic response. As used herein, a "positive therapeutic response" refers to a treatment that produces a beneficial effect, such as reversing, alleviating, improving, inhibiting or delaying a symptom, complication, condition or biochemical sign associated with a disease, as well as preventing the onset, progression, onset, severity or recurrence of a symptom, complication, condition or biochemical sign associated with a disease, such as an improvement in at least one symptom of a disease or disorder, such as cancer. A beneficial effect can take the form of an improvement over a baseline, including an improvement over a measurement or observation made before starting treatment according to the method. For example, a beneficial effect can take the form of delaying, stabilizing, halting or reversing the progression of cancer in a subject at any clinical stage, as evidenced by a reduction or elimination of clinical or diagnostic symptoms of the disease or a marker of cancer. An effective treatment may, for example, reduce tumor size, reduce the presence of circulating tumor cells, reduce or prevent tumor metastasis, slow or stop tumor growth, and / or prevent or slow tumor recurrence or recurrence.

[0185] The term "therapeutic amount" or "effective amount" refers to an amount of a drug or combination of drugs to treat a disease, such as cancer. In some embodiments, a therapeutic amount is an amount sufficient to delay tumor development. In some embodiments, a therapeutic amount is an amount sufficient to prevent or delay tumor recurrence.

[0186] As used herein, an effective amount of an agent or composition is one that, for example, (i) can reduce the number of cancer cells, (ii) can reduce tumor size, (iii) can inhibit, delay, slow to some extent, and stop the invasion of cancer cells into peripheral organs, (iv) can inhibit tumor metastasis, (v) can inhibit tumor growth, (vi) can prevent or delay the onset and / or recurrence of tumors, and / or (vii) can relieve to some extent one or more of the symptoms associated with cancer.

[0187] The effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual being treated, and the ability of the agent or combination of agents to elicit a desired response in the individual, which can be readily assessed by an ordinarily skilled physician or other health care worker.

[0188] An effective amount can be administered to a subject in one or more administrations.

[0189] An effective amount can also include an amount that balances any toxic or detrimental effects of the agent or combination of agents with the beneficial effects.

[0190] The term "agent" refers to a therapeutically active substance, in this case a binding domain or binding moiety of the disclosure, or a pharmaceutical composition of the disclosure.

[0191] As used herein, "comprises" and its conjugations are used in their open-ended sense to mean that the items preceding the word are included, but not excluding items not specifically mentioned.

[0192] The articles "a" and "an" are used herein to refer to one or more of the grammatical object of the article. By way of example, "an element" means one or more elements.

[0193] The reference in this specification to a patent document or other matter is not to be considered an admission that the document or matter was known or that the information contained in it was part of the common general knowledge at the priority date of any of the claims.

[0194] All patent and literature references cited herein are hereby incorporated by reference in their entirety.

[0195] It should be noted that, unless otherwise stated, herein, the amino acid positions assigned to the CDRs and frameworks in the variable regions of an antibody or antibody fragment are designated by the Kabat numbering system (see Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md., 1987 and 1991)). Amino acids in the constant regions are designated by the EU numbering system.

[0196] The accession number is given mainly to provide a method for further identification of the target, and the actual sequence of the bound protein may vary, for example due to mutations in the coding genes, such as those occurring in some cancers. The antigen-binding site of the binding domain or binding moiety of the present disclosure can bind to the antigen and its various variants, such as those expressed by some antigen-positive immune cells or tumor cells. HGNC stands for HUGO Gene nomenclature committee. The number after the abbreviation is the accession number by which information about the gene and the protein encoded by the gene can be retrieved from the HGNC database. Entrez Gene provides an accession number or gene ID by which information about the gene or the protein encoded by the gene can be retrieved from the NCBI (National Center for Biotechnology Information) database. Ensembl provides an accession number by which information about the gene or the protein encoded by the gene can be obtained from the Ensemble database. Ensembl is a collaborative project between EMBL-EBI and the Wellcome Trust Sanger Institute to develop a software system that generates and maintains automated annotations on selected eukaryotic genomes.

[0197] When a gene or protein is referred to herein, it is preferably a reference to the human form of that gene or protein. When a gene or protein is referred to herein, it is a reference to the native gene or protein as well as variants of that gene or protein that can be detected in tumors, cancers, etc. or that can be detected in human tumors, cancers, etc. [Brief description of the drawings]

[0198] The following naming conventions are used herein as follows: In the figures, a reference bivalent monospecific antibody is shown in the format of SEQ ID NO: A / B, where SEQ ID NO: A refers to the heavy chains of both binding domains and SEQ ID NO: B refers to the light chains of both binding domains. A bivalent monospecific MUC1 IgG of the disclosure exemplified herein is shown in the format of SEQ ID NO: A, which refers to the heavy chain variable regions of both binding domains, comprising a light chain of SEQ ID NO: 217, and CH1, hinge, CH2, and CH3 regions of SEQ ID NOs: 223, 222, 224, and 225, respectively.

[0199] [Figure 1] Schematic diagram of MUC1 structure. A) Normal MUC1 structure; B) Abnormal MUC1 structure (taken from Figure 1 in Gao T. et al. Biomed Pharmacother. 2020). Cancer-associated (CA) MUC1 epitopes include exposed core peptide, MUC1-Tn, and MUC1-sTn. [Figure 2-1] FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Figure 2-2] FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Figure 2-3] FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Figure 2-4] FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Figure 2-5]FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Figure 2-6] FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Diagram 2-7] FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Figure 2-8]FACS data showing specificity and relative affinity of MUC1 IgG for MCF7 cells (graphs A, C, E, G, I, K, M, and O) compared to MCF10A cells (graphs B, D, F, H, J, L, N, and P). MUC1 IgG includes core binder (CB), Tn binder (TnB), and (S)Tn binder (SEQ ID NO:). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AP) and SEQ ID NO: 212 / 213 (OP). X-axis: concentration of IgG (μg / ml), Y-axis: median PE signal x 104. [Diagram 3] Affinity for MUC1-Tn plotted against the affinity of MUC1-(S)Tn binders to MUC1-STn. X-axis: IgG affinity to MUC1-STn measured by ELISA and expressed as AUC normalized to the reference antibody 5E5 and isotype control analog. Y-axis: Fab affinity to MUC1-Tn measured by ELISA and expressed as AUC normalized to the reference antibody 5E5 and isotype control analog. Squares within circles are antibodies representing two antibody groups based on very similar HCDR1: 1) SEQ ID NO:1, SEQ ID NO:29, SEQ ID NO:45, SEQ ID NO:57, SEQ ID NO:78, 2) SEQ ID NO:5, SEQ ID NO:9, SEQ ID NO:178. [Figure 4-1] 13 is glycopeptide array data providing EC50 values ​​(ug / ml) for MUC1 IgG binding to MUC1-Tn glycopeptides T1-T12 and S1-S12. No value indicated that binding was detectable. [Figure 4-2] 13 is glycopeptide array data providing EC50 values ​​(ug / ml) for MUC1 IgG binding to MUC1-Tn glycopeptides T1-T12 and S1-S12. No value indicated that binding was detectable. [Figure 5-1]FACS data showing affinity of MUC1 IgG for T47D huGalNAc cells expressing MUC1-STn (graphs A-D) and T47D cells expressing MUC1-Tn (graphs E-H). Negative control antibodies are SEQ ID NOs: 216 / 217, positive control antibodies are SEQ ID NOs: 210 / 211 (AH) and SEQ ID NOs: 212 / 213 (D;H). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence x 104. [Figure 5-2] FACS data showing affinity of MUC1 IgG for T47D huGalNAc cells expressing MUC1-STn (graphs A-D) and T47D cells expressing MUC1-Tn (graphs E-H). Negative control antibodies are SEQ ID NOs: 216 / 217, positive control antibodies are SEQ ID NOs: 210 / 211 (AH) and SEQ ID NOs: 212 / 213 (D;H). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence x 104. [Figure 5-3] FACS data showing affinity of MUC1 IgG for T47D huGalNAc cells expressing MUC1-STn (graphs A-D) and T47D cells expressing MUC1-Tn (graphs E-H). Negative control antibodies are SEQ ID NOs: 216 / 217, positive control antibodies are SEQ ID NOs: 210 / 211 (AH) and SEQ ID NOs: 212 / 213 (D;H). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence x 104. [Figure 5-4] FACS data showing affinity of MUC1 IgG for T47D huGalNAc cells expressing MUC1-STn (graphs A-D) and T47D cells expressing MUC1-Tn (graphs E-H). Negative control antibodies are SEQ ID NOs: 216 / 217, positive control antibodies are SEQ ID NOs: 210 / 211 (AH) and SEQ ID NOs: 212 / 213 (D;H). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence x 104. [Figure 6-1]FIG. 13 is FACS data showing affinity of MUC1 IgG for MC38 huMUC1 COSMC KO cells (graphs A, C, D, F, G, I, and J) compared to MC38 huMUC1 cells (graphs B, E, H, and K). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AK) and SEQ ID NO: 212 / 213 (JK). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence×104. [Figure 6-2] FIG. 13 is FACS data showing affinity of MUC1 IgG for MC38 huMUC1 COSMC KO cells (graphs A, C, D, F, G, I, and J) compared to MC38 huMUC1 cells (graphs B, E, H, and K). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AK) and SEQ ID NO: 212 / 213 (JK). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence×104. [Figure 6-3] FIG. 13 is FACS data showing affinity of MUC1 IgG for MC38 huMUC1 COSMC KO cells (graphs A, C, D, F, G, I, and J) compared to MC38 huMUC1 cells (graphs B, E, H, and K). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AK) and SEQ ID NO: 212 / 213 (JK). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence×104. [Figure 6-4] FIG. 13 is FACS data showing affinity of MUC1 IgG for MC38 huMUC1 COSMC KO cells (graphs A, C, D, F, G, I, and J) compared to MC38 huMUC1 cells (graphs B, E, H, and K). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AK) and SEQ ID NO: 212 / 213 (JK). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence×104. [Figure 6-5]FIG. 13 is FACS data showing affinity of MUC1 IgG for MC38 huMUC1 COSMC KO cells (graphs A, C, D, F, G, I, and J) compared to MC38 huMUC1 cells (graphs B, E, H, and K). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AK) and SEQ ID NO: 212 / 213 (JK). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence×104. [Figure 6-6] FIG. 13 is FACS data showing affinity of MUC1 IgG for MC38 huMUC1 COSMC KO cells (graphs A, C, D, F, G, I, and J) compared to MC38 huMUC1 cells (graphs B, E, H, and K). Negative control antibodies are SEQ ID NO: 216 / 217, and positive control antibodies are SEQ ID NO: 210 / 211 (AK) and SEQ ID NO: 212 / 213 (JK). X-axis: concentration of IgG (μg / ml), Y-axis: median fluorescence×104. EXAMPLES

[0200] In the examples used to illustrate the disclosure, but not intended to limit the disclosure in any way, the MUC1-binding domains of the disclosure are characterized in an IgG format, and each MUC1-binding domain comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:218, and a light chain constant region having the amino acid sequence set forth in SEQ ID NO:226, and a Fab format. In the examples used to illustrate the disclosure, but not intended to limit the disclosure in any way, unless otherwise specified, the MUC1 IgG was screened in an IgG1 format, comprising a CH1 having the amino acid sequence set forth in SEQ ID NO:223, a CH2 having the amino acid sequence set forth in SEQ ID NO:224, and a CH3 having the amino acid sequence set forth in SEQ ID NO:225.

[0201] The reference and control antibodies used in the examples were: - Reference antibody 5E5, which is an analogue of the bivalent monospecific humanized antibody 5E5 and comprises two heavy chains having the amino acid sequence shown in SEQ ID NO: 210 and two light chains having the amino acid sequence shown in SEQ ID NO: 211. Humanized 5E5 binds to the MUC1-(s)Tn (GS*T*A) epitope.

[0202] - Reference antibody pancomab, which is an analogue of the bivalent monospecific antibody pancomab and comprises two heavy chains having the amino acid sequences set forth in SEQ ID NO: 212 and two light chains having the amino acid sequences set forth in SEQ ID NO: 213. Pancomab binds to the MUC1-(s)Tn(PDT*RP) epitope.

[0203] - Reference antibody HT186-D11, which is an analogue of the bivalent monospecific antibody HT186-D11 and comprises two heavy chains having the amino acid sequences shown in SEQ ID NO: 214 and two light chains having the amino acid sequences shown in SEQ ID NO: 215. HT186-D11 binds to the MUC1 core (RPAP) epitope.

[0204] - A bivalent, monospecific control anti-STn antibody clone 3F1 (SBH Sciences, Cat. No. SBH-ASTn), which binds to STn.

[0205] -Tn, bivalent monospecific anti-Tn antibody clone 5F4 (SBH Sciences, catalog number SBH-Tn).

[0206] - Bivalent monospecific control antibody VU4H5 (BioKE, Cat. No. 4538S), which binds to the MUC1 core (APDTRPAP) epitope.

[0207] - A bivalent monospecific isotype control IgG comprising two heavy chains having the amino acid sequence as set forth in SEQ ID NO: 216 and two light chains having the amino acid sequence as set forth in SEQ ID NO: 217.

[0208] Example 1 - Generation of MUC1 Fab Antibodies containing the binding domain and heavy chain variable region that binds cancer-associated MUC-1 were obtained by immunizing transgenic mice (MeMo® mice) containing the consensus IGKV1-39 light chain. Several immunization methods were used, including the use of KHL-conjugated human MUC1 40 Tn8 or MUC1 40 Tn 10 Immunization with peptides as well as cells overexpressing human MUC1-(S)Tn was included. Phage display libraries were generated and screened in ELISA and FACS using MUC1 peptides and cell lines to identify Fabs that bind MUC1-Tn and / or MUC1-STn (MUC1-(S)Tn). Binders were then recloned into IgG format for further characterization. The binding domain sequences herein, once characterized and sequenced by the techniques provided herein, can then be obtained by any method known in the art.

[0209] Example 2 - Specificity and relative affinity of MUC1-(S)Tn measured using ELISA A panel of MUC1 IgGs was screened by ELISA to characterize their binding specificity and relative affinity for different MUC1 peptides. Mimetic peptide and secondary antibody only were included as negative assay controls. An isotype control antibody and an analog of the reference antibody 5E5 were included as negative and positive antibody controls, respectively.

[0210] Biotinylated MUC1 and control peptides were captured at the concentrations shown in Table 1 on Maxisorp plates coated with neutravidin (ThermoFisher Scientific, Cat. No. 31000) and incubated for 1 hour at room temperature. MUC1 IgG and control antibodies were diluted in blocking buffer and added at 10, 1, 0.1 and 0.01ug / ml and incubated for 1 hour at room temperature. Samples were then run with diluted HRP-conjugated secondary antibody (Bethyl Laboratories, A80-104P, 1:2000) for 1 hour at room temperature. After each incubation step, three washing steps were performed using PBST. The reaction was stopped using 1M H2SO4 and the signal was developed using TMB peroxidase substrate solution (BD Biosciences, Cat. No. 555214). The plates were read using a microplate reader for AFM. 450 was analyzed. [Table 1]

[0211] The assay is 40 Tn 10 We identified a number of antibodies in the MUC1 IgG panel that bound to the MUC1 core peptide and did not bind mimetic peptides (data not shown). The binding specificity of MUC1-(S)Tn antibodies was characterized by dividing them into three groups: 1) MUC1 core peptide binders (MUC1 40 and MUC1 40 Tn 10 and MUC1 40 STn 10 2) MUC1-Tn binding agents (MUC1 40 Tn 10 Binds to MUC1 40 STn 10 ), and 3) MUC1-(S)Tn binders (MUC1 40 Tn 10 and MUC1 40 STn 10 The results were binned into four groups:

[0212] Example 3 - Specificity and relative affinity for MUC1-(S)Tn measured using FACS A panel of MUC1 IgGs was screened on MCF7 cells expressing the cancer-associated MUC1-Tn and MCF10A cells expressing wild-type MUC1. An analogue of the reference antibody pancomab was included as a control for the relative expression of MUC1 in the different cell lines. 293FF (MUC1 negative) cells were included as a negative assay control. An isotype control antibody and an analogue of the reference antibody 5E5 were included as negative and positive antibody controls, respectively. The MUC1 IgG panel and control antibodies were titrated using eight 4-fold serial dilutions starting at 10ug / ml. Binding to 293FF cells was tested at 10ug / ml.

[0213] MCF7 cells (DSMZ, ACC115), MCF10A cells (ATCC, Cat. No. CRL-10317), or 293FF cells (Invitrogen, p / n51-0029) were incubated with MUC1 and control antibodies diluted in FACS buffer (PBS+0.5% BSA+2mM EDTA) for 30 minutes on ice, followed by two washes with ice-cold FACS buffer and staining with anti-human IgG-PE (Invitrogen, #H10104) at 1:100. Binding was measured using iQue Screener PLUS. Analysis was performed using IntelliCyt ForeCyt® software. Mean fluorescence intensity (MFI) values ​​for each MUC1 antibody were plotted against the concentration of IgG, and the area under the curve (AUC) was calculated based on normalization using isotype antibodies and analogs of the reference antibody 5E5 as negative and positive antibody controls, respectively.

[0214] The results are shown in Figure 2. The positive and negative control antibodies showed binding to MCF7, MCF10A, and 293FF cells as expected. MUC1 core peptide binders (CB) bound to both MCF7 and MCF10A cells, and some showed low binding to 293FF cells. MUC1-(S)Tn binders (SEQ ID NO:) bind specifically to MCF7 but not MCF10A cells. MUC1-Tn binders (TnB) bind specifically to MCF7 but not MCF10A cells, however with lower affinity compared to MUC1-(S)Tn binders. The affinity of MUC1-(S)Tn binders for MCF7 cells varied, with many antibodies showing higher binding signals than analogs of the reference antibody 5E5.

[0215] Example 4 - MUC1 measured using ELISA 40 Tn 10 and MUC1 40 STn 10 Affinity of MUC1 Fab panel to A panel of MUC1-(S)Tn IgGs was subjected to GingisKHAN digestion to generate Fab (>99% monomer). Biotinylated MUC1 40 Tn 10 and MUC1 40 STn 10 was captured on neutravidin coated plates at 2 μg / ml. A Fab fragment of an analog of the reference antibody 5E5 was included as a positive control antibody, and a Fab fragment of an isotype control antibody was included as a negative control antibody.

[0216] A panel of MUC1-(S)Tn Fabs and control Fabs were serially diluted using eight 10-fold serial dilutions starting at 10ug / ml and incubated at room temperature for 1 hour, followed by incubation with diluted HRP-conjugated secondary antibody (Becton Dickinson, Cat. No. 555788) for 1 hour at room temperature. After each incubation step, three washing steps were performed using PBST. The reaction was stopped using 1M H2SO4 and the signal was developed using TMB peroxidase substrate solution (BD Biosciences, Cat. No. 555214). The plate was read using a microplate reader for 30 min at 37°C. 450 was analyzed.

[0217] MUC1-(S)Tn Fab 40 Tn 10 and MUC1 40 STn 10 The affinity of the Fabs for MUC1-Tn and MUC1-STn is similar to that of IgG (data not shown). A general correlation in affinity was found for the MUC1-Tn and MUC1-STn peptides (see FIG. 3). Some clones show high affinity for MUC1-Tn and MUC1-STn. Within this group, many of the Fabs showing the highest binding affinity for MUC1-Tn and MUC1-STn share the same HCDR1 sequence (boxed in FIG. 3).

[0218] Example 5 - Glycopeptide array A panel of MUC1 IgGs was screened on a glycopeptide array to determine their binding to the O-glycopeptides listed in Table 2. Print buffer was included as a negative assay control. Positive assay controls were human IgG and mouse IgG. Control antibodies included analogs of reference antibody 5E5, analogs of reference antibodies VU4H5, 5F4, and 3F1. MUC1 and control antibodies were titrated using eight 4-fold serial dilutions starting at 10ug / ml.

[0219] O-glycan array assay was performed according to the manual instructions (Z Biotech, LLC). The array was blocked using Glycan Array Blocking Buffer (GAAB, Z Biotech item no. 10106) for 30 minutes. It was then washed three times using TBS-T based Glycan Array Assay Buffer (GAAB, Z Biotech item no. 10107). MUC1 IgG and control antibodies were diluted in GAAB ranging from 10 μg / ml to 0.6 ng / ml and then directly applied to the array. The array was covered with adhesive film and shaken at 80 rpm for 1 hour at room temperature. The array was then washed again three times with GAAB. The detection antibodies, Cy3-conjugated anti-human IgG and Cy3-conjugated anti-mouse IgG, were diluted in GAAB and applied to the array. It was covered with light and shaken at 80 rpm for 1 hour at room temperature, then washed three times with GAAB and two times with MilliQ water. The arrays were read using an Innopsys InnoScan 710 microarray scanner equipped with a high power laser at 1 PMT. Software was used to detect each spot on the array and calculate the relative fluorescence unit (RFU) intensity of each spot. Background RFU was subtracted from the RFU value of each spot. The median spot value for each glycan was determined and graphed in the provided report. [Table 2]

[0220] All control antibodies bound to the epitopes described. Results for MUC1 IgG are shown in Figure 4. MUC1 IgG, previously identified as a MUC1-(S)Tn binder, showed strong binding to peptides T4, T9, T11, S4, S9, and S11. All of these peptides contain modifications of the threonine residue in the VTSA motif, either a Tn modification (α-GalNAc glycosylation) or a STn modification (Neu5Ac-α(2-6)-GalNAc glycosylation). None of the other peptides contain a modification at this position, and the MUC1-(S)Tn binder does not bind to them, with the exception of peptide T8. MUC1-(S)Tn binders also bind peptides when, in addition to the (S)Tn modification of the threonine residue in the VTSA motif, the peptide contains a Tn or STn modification of a serine residue in the VTSA motif (T9, S9), or a Tn or STn modification of a threonine residue in the PDTR motif (T11, S11).

[0221] MUC1 IgG, previously identified as a MUC1-Tn binder, showed strong binding to peptides T2, T7, and T10. All of these peptides contain a Tn modification (α-GalNAc glycosylation) of a serine residue in the GSTA motif. None of the other peptides contain a modification at this position, and the MUC1-(S)Tn binder does not bind to those peptides. The MUC1-Tn binder also binds peptides if, in addition to a Tn modification of a serine residue in the GSTA motif, the peptide contains a Tn modification of a threonine residue in the GSTA motif (T7), or a Tn modification of a threonine residue in the GSTA motif and a Tn modification of a threonine residue in the PDTR motif (T10).

[0222] Example 6 - Affinity of MUC1 IgG to T47D huGalNAc Cells MUC1 IgG was screened for binding to T47D huGalNAc cells stably expressing human MUC1-STn and T47D WT cells expressing moderate levels of MUC-TN. An isotype control antibody was included as a negative control antibody, and an analog of the reference antibody 5E5 was included as a positive control antibody. An analog of the reference antibody pancomab was included as a control for the relative expression of MUC1 in different cell lines. Additional control antibodies included 3F1 and 5F4. MUC1, isotype control, analog of 5E5, and analog of the pancomab antibody were titrated using eight 4-fold serial dilutions starting at 10ug / ml, with 3F1 and 5F4 used at 10ug / ml.

[0223] T47D cells (Sigma-Aldrich, Cat. 85102201-1VL) and T47D huGalNAc cells (generated by stably transfecting T47D cells with a plasmid encoding ST6GALNAC1 (Accession No. Q9NSC7; Uniprot)) were incubated with MUC1 IgG and control antibodies diluted in FACS buffer (PBS+0.5% BSA+2 mM EDTA) for 30 min on ice, followed by two washes with ice-cold FACS buffer and staining with anti-human IgG-PE (Invitrogen, Cat. No. H10104) at 1:100 (for MUC1, isotype control, analog of 5E5, and analog of pancomab antibody samples) or anti-mouse IgG-PE (Invitrogen, Cat. No. M30004-4) at 1:400 (for 3F1 and 5F4 antibody samples). Binding was measured using an iQue Screener PLUS. Analysis was performed using IntelliCyt ForeCyt® software. The MFI values ​​of each MUC1 antibody were plotted against the concentration of IgG, and the area under the curve (AUC) was calculated based on normalization using an isotype control antibody and an analog of the reference antibody 5E5 as negative and positive antibody controls, respectively.

[0224] The results are shown in Figure 5. The panel of MUC1(S)Tn binders shows a range of binding affinities to T47D huGalNAc cells. Several antibodies show higher maximal binding than analogs of the reference antibody 5E5. Affinity to T47D huGalNAc cells correlates well with affinity to the MUC1-STn peptide.

[0225] The panel of MUC1-(S)Tn binders shows a range of binding affinities for T47D WT cells. Most antibodies show higher maximum binding than analogs of the reference antibody 5E5, which corresponds to data obtained with MCF7 cells. The affinity for T47D WT cells is consistent with that of MUC1. 40 Tn 10 It correlates better with affinity for the peptide.

[0226] Example 7 - Affinity of MUC1 IgG to MC38 Cells MUC1 IgG was screened for binding to MC38 huMUC1 COSMC KO cells expressing human MUC1-Tn, MC38 huMUC1 cells expressing normal human MUC1 glycoforms, and MC38 WT cells not expressing human MUC1. An isotype control antibody was included as a negative control antibody, and an analog of the reference antibody 5E5 was included as a positive control antibody. An analog of the reference antibody pancomab was included as a control for the relative expression of MUC1 in the different cell lines. Additional control antibodies included 3F1 and 5F4. MUC1 IgG, isotype control, analog of 5E5, and analog of pancomab were titrated using eight 4-fold serial dilutions starting at 10ug / ml, with 3F1 and 5F4 used at 10ug / ml.

[0227] MC38 huMUC1 COSMC KO cells were generated by stably transfecting MC38 huMUC1 cells (accession number: CVCL_5l38; Uniprot) with human MUC1 and knocking out the mouse COSMC (C1galt1c1) gene (accession number: ENSMUST00000058265.7; Ensemble). Cells were incubated with MUC1 IgG or control antibodies diluted in FACS buffer (PBS+0.5% BSA+2mM EDTA) for 30 minutes on ice, followed by two washes with ice-cold FACS buffer and staining with secondary antibodies anti-human IgG-PE (Invitrogen, Cat. No. H10104) at 1:100 (for MUC1, isotype control, analog of 5E5, and analog of pancomab antibody samples) or anti-mouse IgG-PE (Invitrogen, Cat. No. M30004-4) at 1:400 (for 3F1 and 5F4 antibody samples). Binding was measured using iQue Screener PLUS. Analysis was performed using IntelliCyt ForeCyt® software. The MFI values ​​of each huMUC1-(S)Tn clone were plotted against the concentration of IgG, and the area under the curve (AUC) was calculated based on normalization using an isotype control antibody and an analog of the reference antibody 5E5 as negative and positive antibody controls, respectively.

[0228] The results are shown in Figure 6. The positive and negative control antibodies function as expected in MC38 huMUC1 COSMC KO cells, MC38 huMUC1 cells, and MC38 WT cells. The MUC1 antibodies do not bind to MC38 WT cells, except for the antibody containing the heavy chain variable region with SEQ ID NO: 178. However, this antibody did not bind to the CALR WT negative control peptide or 293FF WT cells. The panel of MUC1-(S)Tn binders shows high binding signals to MC38 huMUC1 COSMC KO cells. The panel of MUC1-(S)Tn binders shows very low binding signals to MC38 huMUC1 cells, indicating specificity for MUC1-(S)Tn. array SEQ ID NO:1 - Heavy chain variable region QVQLVESGAEVKKPGASVRLSCKASGYSFIHYYLHYVRQAPGQGLEWMGVINPFDGSTDYAQKFHGRVTLTRDTSASTVFMELSSLGSEDTAVYFCTRDNMIGYVLFDYWGLGTLVTVSS SEQ ID NO:2 - Heavy chain CDR1 HYYLH SEQ ID NO:3 - Heavy chain CDR2 VINPFDGSTDYAQKFHG SEQ ID NO:4 - Heavy chain CDR3 DNMIGYVLFDY SEQ ID NO:5 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKTSGYTFTRYYIQWVRQAPGQGLEWMGVINPYDGSTNYAQKFQGRVTVTRDTSTFTVYMELSSLRSEDTAVYYCARDYMRGYVIFDYWGQGTLVTVSS SEQ ID NO:6 - Heavy chain CDR1 RYYIQ SEQ ID NO:7 - Heavy chain CDR2 VINPYDGSTNYAQKFQG SEQ ID NO:8 - Heavy chain CDR3 DYMRGYVIFDY SEQ ID NO:9 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFNRHYIQWVRQAPGQGLEWMGTINPYDGSTHYAQKFQGRVTLTRDTSTTTVYMELSSLRSEDTAVYYCARDYMIGYVVFDYWGQGTLVTVSS SEQ ID NO:10 - Heavy chain CDR1 RHYIQ SEQ ID NO:11 - Heavy chain CDR2 TINPYDGSTHYAQKFQG SEQ ID NO:12 - Heavy chain CDR3 DYMIGYVVFDY SEQ ID NO:13 - Heavy chain variable region QVQLVQSGAEVKKPGASLKVSCKASGYTFTNYYIQWVRQAPGQGLEWMGVINPYDGSTNYAQKFQGRVTLTRDTSTTTVYMELSSLRSDDTAVYYCARDYMIGYVVFDYWGQGTLVTVSS SEQ ID NO:14 - Heavy chain CDR1 NYYIQ SEQ ID NO:15 - Heavy chain CDR2 VINPYDGSTNYAQKFQG SEQ ID NO:16 - Heavy chain CDR3 DYMIGYVVFDY SEQ ID NO:17 - Heavy chain variable region QVQLVQSGAEVKKPGASVRVSCKASGYPFINYYIQWVRQAPGQGLEWMGVVNPYDGSTNYAQKFQGRVSITRDASTSTVFMELNSLRSEDTAVYYCARDSMLGHVIFDFWGQGTLVTVSS SEQ ID NO:18 - Heavy chain CDR1 NYYIQ SEQ ID NO:19 - Heavy chain CDR2 VVNPYDGSTNYAQKFQG SEQ ID NO:20 - Heavy chain CDR3 DSMLGHVIFDF SEQ ID NO:21 - Heavy chain variable region QVQLVQSGAEVRKPGASVKFSCKASGYSFTHYYVHWVRQAPGQGLEWMGVINPFDSSTNYARKFQGRVTMTRDTSTTTVYMDLSSLRSEDTAVYFCARDAMEGDSYFDYWGQGTLVTVSS SEQ ID NO:22 - Heavy chain CDR1 HYYVH SEQ ID NO:23 - Heavy chain CDR2 VINPFDSSTNYARKFQG SEQ ID NO:24 - Heavy chain CDR3 DAMEGDSYFDY SEQ ID NO:25 - Heavy chain variable region QVQLVESGAEVKKPGASVKVSCKASGYTFARYYVHWVRQAPGQGLEWMGLINPYGGATNYAQNFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDAMGGDSYFDYWGQGTLVTVSS SEQ ID NO:26 - Heavy chain CDR1 RYYVH SEQ ID NO:27 - Heavy chain CDR2 LINPYGGATNYAQNFQG SEQ ID NO:28 - Heavy chain CDR3 DAMGGDSYFDY SEQ ID NO:29 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYSFIHYYIHWVRQAPGQGLEWMGVINPFDGSTNYAQKFQDRVTVTRDTSTSTVFMDLSSLRSEDTAVYYCARDNMIGYVLFDDWGQGTLVTVSS SEQ ID NO:30 - Heavy chain CDR1 HYYYH SEQ ID NO:31 - Heavy chain CDR2 VINPFDGSTNYAQKFQD SEQ ID NO:32 - Heavy chain CDR3 DNMIGYVLFDD SEQ ID NO:33 - Heavy chain variable region QVQLVQSGAEVKKPGASVRVSCKASGYPFINYYIQWVRQAPGQGLEWMGVINPFDGSTNYAQKFQDRVTVTRDTSTSTVFMDLSSLRSEDTAVYYCARDNMIGYVLLDYWGQGTLVTVSS SEQ ID NO:34 - Heavy chain CDR1 NYYIQ SEQ ID NO:35 - Heavy chain CDR2 VINPFDGSTNYAQKFQD SEQ ID NO:36 - Heavy chain CDR3 DNMIGYVLLDY SEQ ID NO:37 - Heavy chain variable region QVQLVQSGAEVKKPGASVTVSCKTSGYTFTSYYIHWLRQAPGQGLEWMGVINPFGGATNYAQKFQGRVTMTRDTSTITVYMELSSLRSEDTAVYYCARDAMGGDSHFDHWGRGTLVTVSS SEQ ID NO:38 - Heavy chain CDR1 SYYIH SEQ ID NO:39 - Heavy chain CDR2 VINPFGGATNYAQKFQG SEQ ID NO:40 - Heavy chain CDR3 DAMGGDSHFDH SEQ ID NO:41 - Heavy chain variable region QVQLVQSGAEVKEPGASMTLSCKTSGYTFISNYIHWLRQAPGQGLEWLGVINPFGGATNYAQKFQGRVTMTRDTSTITVYMELSSLRSEDTAVYYCARDAMGGDSHFDYWGQGTLVTVSS SEQ ID NO:42 - Heavy chain CDR1 SNYIH SEQ ID NO:43 - Heavy chain CDR2 VINPFGGATNYAQKFQG SEQ ID NO:44 - Heavy chain CDR3 DAMGGDSHFDY SEQ ID NO:45 - Heavy chain variable region QVQLVESGTEVKKPGASVKVSCKASGYSFIHYYIHWVRQAPGRGLEWMGVINPFDGSTNSAQNFQGRVTVTRDTSTSTVFMDLSSLRSEDTAVYYCARDNMLGYVLFDHWGQGTLVTVSS SEQ ID NO:46 - Heavy chain CDR1 HYYYH SEQ ID NO:47 - Heavy chain CDR2 VINPFDGSTNSAQNFQG SEQ ID NO:48 - Heavy chain CDR3 DNMLGYVLFDH SEQ ID NO:49 - Heavy chain variable region QVQLVESGAEVKKPGASVKVSCKASGYTFTRYYLHWVRQAPGQGLEWMGVINPYGGATNYAQKFQGRVTLTRDTSTSTVYMELNSLRSEDTAVYFCARDAMEGNSYFDHWGPGTLVTVSS SEQ ID NO:50 - Heavy chain CDR1 RYYLH SEQ ID NO:51 - Heavy chain CDR2 VINPYGGATNYAQKFQG SEQ ID NO:52 - Heavy chain CDR3 DAMEGNSYFDH SEQ ID NO:53 - Heavy chain variable region QVQLVQSGAEVKKPGASMTVSCKTSGYTFISYYIHWLRQAPGQGLEWLGVINPFGGATNYAQKFQGRVTMTRDTSTITVYMELSSLRSEDTAVYYCARDAMGGDSHFDFWGQGTLVTVSS SEQ ID NO:54 - Heavy chain CDR1 SYYIH SEQ ID NO:55 - Heavy chain CDR2 VINPFGGATNYAQKFQG SEQ ID NO:56 - Heavy chain CDR3 DAMGGDSHFDF SEQ ID NO:57 - Heavy chain variable region QVQLVESGTEVKKPGASVKVSCKASGYSFIHYYIHWVRQAPGRGLEWMGVINPFDGSTNYAQNFQGRVTVTRDTSTSTVFMDLSSLRSEDTAVYYCARDNMIGYVLFDHWGQGTLVTVSS SEQ ID NO:58 - Heavy chain CDR1 HYYYH SEQ ID NO:60 - Heavy chain CDR2 VINPFDGSTNYAQNFQG SEQ ID NO:61 - Heavy chain CDR3 DNMIGYVLFDH SEQ ID NO:62 - Heavy chain variable region QVQLVESGAEVKKPGASVKVSCKASGYSFTSYYIQWVRQAPGQGLEWLAVINPIDGSTNYAQKFQGRVTVTRDTSTSTVYMELSSLRSEDTAVYYCARDYMRGFVVFDYWGQGTLVTVSS SEQ ID NO:63 - Heavy chain CDR1 SYYIQ SEQ ID NO:64 - Heavy chain CDR2 VINPIDGSTNYAQKFQG SEQ ID NO:65 - Heavy chain CDR3 DYMRGFVVFDY SEQ ID NO:66 - Heavy chain variable region QVQLVQSGAEVKKPGASVRVSCKASGYTFTNYYIHWVRQAPGHGLTWMGVINPFDSSTDYAQKFQGRVTMTRDTSTSTVYMDLSSLRSEDTAVYYCARDYMRGHVVFDYWGQGTLVTVSS SEQ ID NO:67 - Heavy chain CDR1 NYYIH SEQ ID NO:68 - Heavy chain CDR2 VINPFDSSTDYAQKFQG SEQ ID NO:69 - Heavy chain CDR3 DYMRGHVVFDY SEQ ID NO:70 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYAFPNYYIHWVRQAPGQGLEWMGVINPYGGSTNYAQKFQGRVTMTRGTSTSTVYLELSSLRSEDTAVYYCARDAMKGDSFFDYWGQGTLVTVSS SEQ ID NO:71 - Heavy chain CDR1 NYYIH SEQ ID NO:72 - Heavy chain CDR2 VINPYGGSTNYAQKFQG SEQ ID NO:73 - Heavy chain CDR3 DAMKGDSFFDY SEQ ID NO:74 - Heavy chain variable region QVQLVQSGAEVKKPGASVQVSCKASGYTFINYYLQWVRQAPGQGLEWMGTINPFDGSTHYEQNFQGRVTMTRDTSTNTVYMELNGLRSEDTAVYYCARDHMIGYILFDYWGQGTTVTVSS SEQ ID NO:75 - Heavy chain CDR1 NYYLQ SEQ ID NO:76 - Heavy chain CDR2 TINPFDGSTHYEQNFQG SEQ ID NO:77 - Heavy chain CDR3 DHMIGYILFDY SEQ ID NO:78 - Heavy chain variable region QVQLVQSGAEVKKPGTSVKVSCKASGYSFIHYYIHWVRQAPGQGLEWVGVINPFDGSTNYAQKFQGRVTVTRDTSTSAVFMDLSSLRSEDTAVYYCARDNMIGYVLFDYWGQGTLVTVSS SEQ ID NO:79 - Heavy chain CDR1 HYYYH SEQ ID NO:80 - Heavy chain CDR2 VINPFDGSTNYAQKFQG SEQ ID NO:81 - Heavy chain CDR3 DNMIGYVLFDY SEQ ID NO:82 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGVINPYDSSTNYAQKFQGRVTMTRDTSTSTVFMDLSSLRSEDTAVYYCARDNMIGYVLFDYWGQGTLVTVSS SEQ ID NO:83 - Heavy chain CDR1 SYYIH SEQ ID NO:84 - Heavy chain CDR2 VINPYDSSTNYAQKFQG SEQ ID NO:85 - Heavy chain CDR3 DNMIGYVLFDY SEQ ID NO:86 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYPFINYYIQWVRQAPGQGLEWMGVINPFDGSTNYAQKFQGRVTVTRDTSTSTVFMDLSSLRSEDTAVYYCARDNMIGYVLFDYWGQGTLVTVSS SEQ ID NO:87 - Heavy chain CDR1 NYYIQ SEQ ID NO:88 - Heavy chain CDR2 VINPFDGSTNYAQKFQG SEQ ID NO:89 - Heavy chain CDR3 DNMIGYVLFDY SEQ ID NO:90 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFINHYIHWVRQAPGQGLEWMGVINPFDGSTNYAQKFQGRVTVTRDTSTSTVFLDLSSLRSEDTAVYYCARDNMIGYVLFDYWGQGTLVTVSS SEQ ID NO:91 - Heavy chain CDR1 NHYIH SEQ ID NO:92 - Heavy chain CDR2 VINPFDGSTNYAQKFQG SEQ ID NO:93 - Heavy chain CDR3 DNMIGYVLFDY SEQ ID NO:94 - Heavy chain variable region QVQLVQSGAEVKKPGSSVKVSCKASGYTFNSYYIHWVRQAPGQGLTWMGVINPFDGSTDYAQKFQGRVTMTRDTSTSTVYMDLSSLRSEDTAVYYCARDYMRGYVVFDYWGRGTLVTVSS SEQ ID NO:95 - Heavy chain CDR1 SYYIH SEQ ID NO:96 - Heavy chain CDR2 VINPFDGSTDYAQKFQG SEQ ID NO:97 - Heavy chain CDR3 DYMRGYVVFDY SEQ ID NO:98 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIQWLRQAPGQGLEWMGVINPTGGATNYAQKFQGRVTMTRETSTSMVHMELSSLRSEDTAVYYCARDYMRGYVVFDYWGQGTLVTVSS SEQ ID NO:99 - Heavy chain CDR1 SYYIQ SEQ ID NO:100 - Heavy chain CDR2 VINPTGGATNYAQKFQG SEQ ID NO:101 - Heavy chain CDR3 DYMRGYVVFDY SEQ ID NO:102 - Heavy chain variable region QVQLVQSGAEVKKSGASVKVSCKASGYPFISYYIHWLRQAPGQGLTWMGVINPFDGSTDYAQKFQGRVTVTRDTSTSTVYMDLSSLRADDTAIYYCARDYMRGYVVFDYWGQGTLVTVSS SEQ ID NO:103 - Heavy chain CDR1 SYYIH SEQ ID NO:104 - Heavy chain CDR2 VINPFDGSTDYAQKFQG SEQ ID NO:105 - Heavy chain CDR3 DYMRGYVVFDY SEQ ID NO:106 - Heavy chain variable region QVQLVQSGAEMKKPGASVKISCKASGYTFTNYYIQWVRQAPGQGLEWMGVINPYDGSTNYAQRFQGRVTLTRDTSTTTVYMELSSLRSEDTAVYYCARDYMIGYVVFDFWGQGTLVTVSS SEQ ID NO:107 - Heavy chain CDR1 NYYIQ SEQ ID NO:108 - Heavy chain CDR2 VINPYDGSTNYAQRFQG SEQ ID NO:109 - Heavy chain CDR3 DYMIGYVVFDF SEQ ID NO:110 - Heavy chain variable region QVQLVQSGAEMKKPGASVKVSCKASGYTFTNYYIHWVRQAPGQGLEWMGVINPYDGSTNYAQKFQGRVTLTRDTSTTTVYMELSSLRSEDTAVYYCARDYMIGYVVFDFWGQGTLVTVSS SEQ ID NO:111 - Heavy chain CDR1 NYYIH SEQ ID NO:112 - Heavy chain CDR2 VINPYDGSTNYAQKFQG SEQ ID NO:113 - Heavy chain CDR3 DYMIGYVVFDF SEQ ID NO:114 - Heavy chain variable region QVQLVQSGAEMKKPGASVTVSCKASGYTFTNYYIQWVRQAPGQGLEWMGVINPYDGSTNYAQRFQGRVTLTRDTTTTTVNMELSGLRSEDTAVYYCARDYMIGYVVFDFWGQGTLVTVSS SEQ ID NO:115 - Heavy chain CDR1 NYYIQ SEQ ID NO:116 - Heavy chain CDR2 VINPYDGSTNYAQRFQG SEQ ID NO:117 - Heavy chain CDR3 DYMIGYVVFDF SEQ ID NO:118 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIQWVRQAPGQGLEWMGVINPYDGSTNYAQRFQGKITLTRDTSTTTVYMELSSLGSEDTAVYYCARDYMIGYVVFDYWGQGTMVTVSS SEQ ID NO:119 - Heavy chain CDR1 NYYIQ SEQ ID NO:120 - Heavy chain CDR2 VINPYDGSTNYAQRFQG SEQ ID NO:121 - Heavy chain CDR3 DYMIGYVVFDY SEQ ID NO:122 - Heavy chain variable region EVQLLESGAEVKKPGASVKVSCKASGYTFNRYYIHWVRQAPGQGLEWMGVINPYDGSTDYAQKFRDRITMTRDTSTNTVYMDLSSLRSEDTAVYFCARDAMEGDSYFDNWGRGTLVTVSS SEQ ID NO:123 - Heavy chain CDR1 RYYIH SEQ ID NO:124 - Heavy chain CDR2 VINPYDGSTDYAQKFRD SEQ ID NO:125 - Heavy chain CDR3 DAMEGDSYFDN SEQ ID NO:126 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFNRYYLHWVRQAPGQGLEWMGVINPYDGSTNYAQKFRGRVTMTRDTSTNTVYMELSSLRSEDTAVYFCARDAMEGDSYFDNWGQGTTVTVSS SEQ ID NO:127 - Heavy chain CDR1 RYYLH SEQ ID NO:128 - Heavy chain CDR2 VINPYDGSTNYAQKFRG SEQ ID NO:129 - Heavy chain CDR3 DAMEGDSYFDN SEQ ID NO:130 - Heavy chain variable region QVQLVQSGAEVKKPGASVRVSCKASGYTFINYYLQWVRQAPGQGLEWMGTINPFDGSTHYAQKFQGRVTLTRDTSTSTVYMELNSLRSDDTAVYYCARDYMIGYVLFDYWGQGTLVTVSS SEQ ID NO:131 - Heavy chain CDR1 NYYLQ SEQ ID NO:132 - Heavy chain CDR2 TINPFDGSTHYAQKFQG SEQ ID NO:133 - Heavy chain CDR3 DYMIGYVLFDY SEQ ID NO:134 - Heavy chain variable region QVQLVQSGAEVKKPGASVEVSCKASGYTFINYYIHWVRQAPGQGLEWMGVINPFDGSTNYAQKFQGRVTVTRDTSTSTVFLDLSSLRPEDTAVYYCARDSMIGYVLFDYWGQGTLVTVSS SEQ ID NO:135 - Heavy chain CDR1 NYYIH SEQ ID NO:136 - Heavy chain CDR2 VINPFDGSTNYAQKFQG SEQ ID NO:137 - Heavy chain CDR3 DSMIGYVLFDY SEQ ID NO:138 - Heavy chain variable region QVQLVQSGAEVKKPGASVRVSCKASGYTFINYYLQWVRQAPGQGLEWMGTINPFDGSTHYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDSMIGYVLFDYWGQGTLVTVSS SEQ ID NO:139 - Heavy chain CDR1 NYYLQ SEQ ID NO:140 - Heavy chain CDR2 TINPFDGSTHYAQKFQG SEQ ID NO:141 - Heavy chain CDR3 DSMIGYVLFDY SEQ ID NO:142 - Heavy chain variable region QVQLVQSGAEVKKPGASVMLSCKASGYIFTSYYIQWVRQAPGQGLEWMGVVNPYDGSTNYAQKFQGRVSITRDTSTSTVFMELNSLRSEDTAVYYCARDSMLGHVIFDFWGQGTLVTVSS SEQ ID NO:143 - Heavy chain CDR1 SYYIQ SEQ ID NO:144 - Heavy chain CDR2 VVNPYDGSTNYAQKFQG SEQ ID NO:145 - Heavy chain CDR3 DSMLGHVIFDF SEQ ID NO:146 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYIHWVRQAPGQGLEWMGVINPYGGSTNYAQKFQGRVTMTRDTSTRIVYMDLSSLRSEDTAVYYCARDAMEGDSYFDYWGQGTLVTVSS SEQ ID NO:147 - Heavy chain CDR1 SYYIH SEQ ID NO:148 - Heavy chain CDR2 VINPYGGSTNYAQKFQG SEQ ID NO:149 - Heavy chain CDR3 DAMEGDSYFDY SEQ ID NO:150 - Heavy chain variable region QVQLVQSGAEVKTPGASVKVSCKASGYTFTNYYIQWVRQAPGQALEWMGVINPYDGSTHYAQKFQGRVTLTRDTSTTTVYMDLSSLRSEDAAVYYCARDYMLGYVVFDYWGQGTLVTVSS SEQ ID NO:151 - Heavy chain CDR1 NYYIQ SEQ ID NO:152 - Heavy chain CDR2 VINPYDGSTHYAQKFQG SEQ ID NO:153 - Heavy chain CDR3 DYMLGYVVFDY SEQ ID NO:154 - Heavy chain variable region QVQLVQSGAEVKKSGASVKVSCKASGYIFTSYYIQWVRQAPGQGLEWMGVINPFDGSTDYAQKFQGRVTVTRDTSTTTVFMELSSLRSEDTAVYYCARDNMLGYVLFDYWGQGTLVTVSS SEQ ID NO:155 - Heavy chain CDR1 SYYIQ SEQ ID NO:156 - Heavy chain CDR2 VINPFDGSTDYAQKFQG SEQ ID NO:157 - Heavy chain CDR3 DNMLGYVLFDY SEQ ID NO:158 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGVINPFDGSTNYAQKFQGRVTVTRDTATTTVFMDLSSLRSEDTAVYYCARDNMLGYVLFDYWGQGTLVTVSS SEQ ID NO:159 - Heavy chain CDR1 SYYMH SEQ ID NO:160 - Heavy chain CDR2 VINPFDGSTNYAQKFQG SEQ ID NO:161 - Heavy chain CDR3 DNMLGYVLFDY SEQ ID NO:162 - Heavy chain variable region QVQLVQSGAEVKKPGASVMLSCKASGYIFTSYYIQWVRQAPGQGLEWMGVVNPYDGSTNYAQKFQGRVTITRDTSTSTVFMELSSLRSEDTAVYYCARDNMLGHVIFDFWGQGTLVTVSS SEQ ID NO:163 - Heavy chain CDR1 SYYIQ SEQ ID NO:164 - Heavy chain CDR2 VVNPYDGSTNYAQKFQG SEQ ID NO:165 - Heavy chain CDR3 DNMLGHVIFDF SEQ ID NO:166 - Heavy chain variable region QVQLVESGAEVKKPGASVKVSCKASGYTFNRYYIHWVRQAPGQGLEWMGVINPSDGSTNYAQKFRGRITMTRDTSTNIVYMELSSLRSEDTAVYFCARDAMGGDSYFDNWGQGTLVTVSS SEQ ID NO:167 - Heavy chain CDR1 RYYIH SEQ ID NO:168 - Heavy chain CDR2 VINPSDGSTNYAQKFRG SEQ ID NO:169 - Heavy chain CDR3 DAMGGDSYFDN SEQ ID NO:170 - Heavy chain variable region QVQLVQSGAEVKKPGASVQVSCKASGYTFINYYLQWVRQAPGQGLEWMGTINPFDGSTHYAQKFQGRVTMTRDTSTNTVYMELNSLRSEDTAVYYCARDRMIGYVLFDYWGQGTLVTVSS SEQ ID NO:171 - Heavy chain CDR1 NYYLQ SEQ ID NO:172 - Heavy chain CDR2 TINPFDGSTHYAQKFQG SEQ ID NO:173 - Heavy chain CDR3 DRMIGYVLFDY SEQ ID NO:174 - Heavy chain variable region EVQLVESGAEVKKPGASVKVSCKASGYTFNRYYLHWVRQAPGQGLEWMGVINPYDGSTNYAQKFRGRITMTRDTSTNTVYMELSSLRSEDTAVYFCARDAMEGDSYFDKWGQGTLVTVSS SEQ ID NO:175 - Heavy chain CDR1 RYYLH SEQ ID NO:176 - Heavy chain CDR2 VINPYDGSTNYAQKFRG SEQ ID NO:177 - Heavy chain CDR3 DAMEGDSYFDK SEQ ID NO:178 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFNRHYIQWVRQAPGQGLEWMGTINPYDGSTFYAQKFQDRVTMTRDTSTSTVYMDLNSLKSEDTAVYYCARDYMRGHVLFDYWGQGTLVTVSS SEQ ID NO:179 - Heavy chain CDR1 RHYIQ SEQ ID NO:180 - Heavy chain CDR2 TINPYDGSTFYAQKFQD SEQ ID NO:181 - Heavy chain CDR3 DYMRGHVLFDY SEQ ID NO:182 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYSFTYSYIQWVRLAPGRGLEWMGVINPYDGSTDYAQKFQGRVTLTRDTSTTTVYMELSSLTSEDTAVYYCARDFMIGYVVFDYWGQGTLVTVSS SEQ ID NO:183 - Heavy chain CDR1 YSYIQ SEQ ID NO:184 - Heavy chain CDR2 VINPYDGSTDYAQKFQG SEQ ID NO:185 - Heavy chain CDR3 DFMIGYVVFDY SEQ ID NO:186 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFNRYYIHWVRQAPGQGLEWMGVINPYDGSTNYAQKFRGRITMTRDTSTNTVYMDLSSLRSEDTAVYFCARDAMEGDSYLDNWGRGTLVTVSS SEQ ID NO:187 - Heavy chain CDR1 RYYIH SEQ ID NO:188 - Heavy chain CDR2 VINPYDGSTNYAQKFRG SEQ ID NO:189 - Heavy chain CDR3 DAMEGDSYLDN SEQ ID NO:190 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYAFTNYYIHWVRQAPGHGLTWMGVINPFDSSTDFAQKFQGRLTMTRDTSTSTVYMDLSSLRSEDTAVYYCARDYMRGHVVFDNWGQGTLVTVSS SEQ ID NO:191 - Heavy chain CDR1 NYYIH SEQ ID NO:192 - Heavy chain CDR2 VINPFDSSTDFAQKFQG SEQ ID NO:193 - Heavy chain CDR3 DYMRGHVVFDN SEQ ID NO:194 - Heavy chain variable region QVQLVQSGAEVKKPGTSVKVSCTASGYTFTNYYIQWVRQAPGQGLEWLGVINPYDGSTDYAQKFQGRVTLTRDTSTTTVYMELSSLRSEDTAVYYCARDYMLGYVVFDFWGQGTLVTVSS SEQ ID NO:195 - Heavy chain CDR1 NYYIQ SEQ ID NO:196 - Heavy chain CDR2 VINPYDGSTDYAQKFQG SEQ ID NO:197 - Heavy chain CDR3 DYMLGYVVFDF SEQ ID NO:198 - Heavy chain variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFINNYIQWVRQAPGQGLEWMGVINPYDGSIHYAQKFQGRVTLTRDTSTTTVYMELSSLRSEDTAVYYCARDYMIGYVVFEYWGQGTLVTVSS SEQ ID NO:199 - Heavy chain CDR1 NNYIQ SEQ ID NO:200 - Heavy chain CDR2 VINPYDGSIHYAQKFQG SEQ ID NO:201 - Heavy chain CDR3 DYMIGYVVFEY SEQ ID NO:202 - Heavy chain variable region QVQLVQSGAEVKNPGASVKFSCKASGYTFINYYLQWLRQAPGQGLEWMGTINPFDGSTSYAQNFQGRVTMTRDTSSTTVYMELNSLKSEDTAVYYCARDSMIGYVLFDSWGQGTLVTVSS SEQ ID NO:203 - Heavy chain CDR1 NYYLQ SEQ ID NO:204 - Heavy chain CDR2 TINPFDGSTSYAQNFQG SEQ ID NO:205 - Heavy chain CDR3 DSMIGYVLFDS SEQ ID NO:206 - Heavy chain variable region QVQLVQSGAEVKKPGASVRVSCKASGYPFINYYIQWVRQAPGQGLEWMGVINPFDGSTNYAQKFQGRVTVTRDTSTSTVFMDLNSLRSEDTAVYYCARDSMIGYVLFDFWGQGTLVTVSS SEQ ID NO:207 - Heavy chain CDR1 NYYIQ SEQ ID NO:208 - Heavy chain CDR2 VINPFDGSTNYAQKFQG SEQ ID NO:209 - Heavy chain CDR3 DSMIGYVLFDF SEQ ID NO:210 - Heavy chain 5E5 analog QVQLVQSGAEVKKTGSSVKVSCKASGYTFTDHAIHWVRQAPGQALEWMGHFSPGNTDIKYNDKFKGRVTLTVDRSMSTAYMELSSLRSEDTAMYYCKTSTFFFDYWGQGTM VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELGRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:211 - Light chain 5E5 analog DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGDQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:212 - Heavy chain vancomab analog EVKLVESGGGLVQPGGSMKLSCVASGFTFSNYWMNWVRQSPEKGLEWVAEIRLKSNNYTTHYAESVKGRFTISRDDSKSSVSLQMNNLRVEDTGIYYCTRHYYFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPCPAPELGRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:213 - Light chain vancomab analog DIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYFFWYLQKPGLSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLELPPTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:214 - Heavy chain HT186-D11 analog QMQLVQSEAELKKPGASVKVSCKASGYSFTGHYMHWVRQAPGQGLEWMGWIDPVTGGTKYAQNFQGWVTMTRDTSIRTAYLELSRLRSDDTAMYYCAREVTGDRGQFDKWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELGRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:215 - Light chain HT186-D11 analog QSVLTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPALVIYYGSNRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDWVFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:216 - Heavy chain isotype control IgG EVQLVETGAEVKKPGASVKVSCKASDYIFTKYDINWVRQAPGQGLEWMGWMSANTGNTGYAQKFQGRVTMTRDTSINTAYMELSSLTSGDTAVYFCARSSLFKTETAPYYHFAL DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK SCDKTHTCPPCPAPELGRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:217 - Light chain isotype control IgG DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:218 - Light chain variable region DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK Light chain CDR1 according to SEQ ID NO: 219-IMGT QSISSY Light chain CDR2 according to SEQ ID NO: 220-IMGT AAS Light chain CDR3 according to SEQ ID NO: 221-IMGT QQSYSTPPT SEQ ID NO:222 - Hinge region EPKSCDKTHTCPPCP SEQ ID NO: 223 - CH1 region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV SEQ ID NO:224-CH2 region APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK SEQ ID NO:225-CH3 region GQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:226-CL region RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 227 - V region VK1-39 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTP SEQ ID NO:228-VK1-39 / JK1 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK SEQ ID NO:229-VK1-39 / JK5 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK Light chain CDR1 according to SEQ ID NO: 230-IMGT QSISSY Light chain CDR2 according to SEQ ID NO: 231-IMGT AAS Light chain CDR3 according to SEQ ID NO: 232-IMGT QQSYSTPPIT SEQ ID NO: 233 - V region VK3-15 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWP SEQ ID NO:234-VK3-15 / JK1 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPWTFGQGTKVEIK Light chain CDR1 according to SEQ ID NO: 235-IMGT QSVSSN Light chain CDR2 according to SEQ ID NO: 236-IMGT GAS Light chain CDR3 according to SEQ ID NO: 237-IMGT QQYNNWPWT SEQ ID NO: 238 - V region VK3-20 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSP SEQ ID NO:239-VK3-20 / JK1 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK Light chain CDR1 according to SEQ ID NO: 240-IMGT QSVSSSY Light chain CDR2 according to SEQ ID NO: 241-IMGT GAS Light chain CDR3 according to SEQ ID NO: 242-IMGT QQYGSSPWT SEQ ID NO: 243-V region VL3-21 SYVLTQPPSVSVAPGETARITCGGDNIGRKSVYWYQQKSGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDGSSDH SEQ ID NO:244-VL3-21 / JL3 SYVLTQPPSVSVAPGETARITCGGDNIGRKSVYWYQQKSGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDGSSDHWVFGGGTKLTVL Light chain CDR1 according to SEQ ID NO: 245-IMGT NIGRKS Light chain CDR2 according to SEQ ID NO: 246-IMGT YDS Light chain CDR3 according to SEQ ID NO: 247-IMGT QVWDGSSDHWV Light chain CDR3 according to SEQ ID NO: 248-IMGT QQSYSTPPT SEQ ID NO:249 PAPGSTAPPAHGVTSAPDTRPAPG

Claims

1. A binding domain that binds to a MUC1 peptide comprising the amino acid sequence set forth in SEQ ID NO:249, wherein the threonine (T) residue at position 14 of the MUC1 peptide comprises an α-GalNAc glycosylation or a Neu5Ac-α(2-6)-GalNAc glycosylation.

2. The binding domain of claim 1, wherein the threonine (T) residue at position 14 of the MUC1 peptide contains an α-GalNAc glycosylation.

3. The binding domain of claim 1, wherein the threonine (T) residue at position 14 of the MUC1 peptide comprises a Neu5Ac-α(2-6)-GalNAc glycosylation.

4. The binding domain of any one of claims 1 to 3, wherein the serine (S) residue at position 15 of the MUC1 peptide further comprises an α-GalNAc glycosylation or a Neu5Ac-α(2-6)-GalNAc glycosylation.

5. The binding domain of claim 4, wherein the serine (S) residue at position 15 of the MUC1 peptide comprises an α-GalNAc glycosylation.

6. The binding domain of claim 4, wherein the serine (S) residue at position 15 of the MUC1 peptide comprises a Neu5Ac-α(2-6)-GalNAc glycosylation.

7. 7. The binding domain of any one of claims 1 to 6, which does not bind to a MUC1 peptide comprising the amino acid sequence set forth in SEQ ID NO: 249, which does not contain α-GalNAc glycosylation or Neu5Ac-α(2-6)-GalNAc glycosylation.

8. The binding domain of any one of claims 1 to 7, wherein the binding to the MUC-1 peptide is determined in a glycopeptide array.

9. A binding domain that specifically binds to cancer-associated MUC-1, wherein the binding domain binds to an epitope on MUC1 that contains a VTSA motif in the N-terminal domain of MUC1, and wherein threonine (T) residues are α-GalNAc glycosylated or Neu5Ac-α(2-6)-GalNAc glycosylated.

10. The binding domain of claim 9, wherein the threonine (T) is α-GalNAc glycosylated.

11. The binding domain of claim 9, wherein the threonine (T) is Neu5Ac-α(2-6)-GalNAc glycosylated.

12. The binding domain according to any one of claims 9 to 11, wherein the serine (S) residue is further glycosylated with α-GalNAc or Neu5Ac-α(2-6)-GalNAc.

13. The binding domain of claim 12, wherein the serine (S) residue is α-GalNAc glycosylated.

14. The binding domain of claim 12, wherein the serine (S) residue is Neu5Ac-α(2-6)-GalNAc glycosylated.

15. The binding domain according to any one of claims 9 to 14, wherein the binding to the epitope on MUC1 is determined in a glycopeptide array.

16. A binding domain having binding specificity for cancer-associated MUC1, said binding domain comprising: a) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; b) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; c) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively; d) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively; e) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:18, SEQ ID NO:19, and SEQ ID NO:20, respectively; f) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24, respectively; g) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:26, SEQ ID NO:27, and SEQ ID NO:28, respectively; h) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, respectively; i) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; j) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:38, SEQ ID NO:39, and SEQ ID NO:40, respectively; k) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44, respectively; l) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:46, SEQ ID NO:47, and SEQ ID NO:48, respectively; m) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:50, SEQ ID NO:51, and SEQ ID NO:52, respectively; n) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; o) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:58, SEQ ID NO:60, and SEQ ID NO:61, respectively; p) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:63, SEQ ID NO:64, and SEQ ID NO:65, respectively; q) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:67, SEQ ID NO:68, and SEQ ID NO:69, respectively; r) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; s) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 75, SEQ ID NO: 76, and SEQ ID NO: 77, respectively; t) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:79, SEQ ID NO:80, and SEQ ID NO:81, respectively; u) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 83, SEQ ID NO: 84, and SEQ ID NO: 85, respectively; v) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:87, SEQ ID NO:88, and SEQ ID NO:89, respectively; w) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; x) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:95, SEQ ID NO:96, and SEQ ID NO:97, respectively; y) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:99, SEQ ID NO:100, and SEQ ID NO:101, respectively; z) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 103, 104, and 105, respectively; aa) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 107, SEQ ID NO: 108, and SEQ ID NO: 109, respectively; bb) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; cc) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:115, SEQ ID NO:116, and SEQ ID NO:117, respectively; dd) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 119, SEQ ID NO: 120, and SEQ ID NO: 121, respectively; ee) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 123, SEQ ID NO: 124, and SEQ ID NO: 125, respectively; ff) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 127, SEQ ID NO: 128, and SEQ ID NO: 129, respectively; gg) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 131, 132, and 133, respectively; hh) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 135, SEQ ID NO: 136, and SEQ ID NO: 137, respectively; ii) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 139, SEQ ID NO: 140, and SEQ ID NO: 141, respectively; jj) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 143, SEQ ID NO: 144, and SEQ ID NO: 145, respectively; kk) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 147, 148, and 149, respectively; ll) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 151, SEQ ID NO: 152, and SEQ ID NO: 153, respectively; mm) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 155, SEQ ID NO: 156, and SEQ ID NO: 157, respectively; nn) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 159, 160, and 161, respectively; oo) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 163, 164, and 165, respectively; pp) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 167, 168, and 169, respectively; qq) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 171, 172, and 173, respectively; rr) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 175, 176, and 177, respectively; ss) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 179, 180, and 181, respectively; tt) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 183, 184, and 185, respectively; uu) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 187, 188, and 189, respectively; vv) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO: 191, SEQ ID NO: 192, and SEQ ID NO: 193, respectively; ww) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NO:195, SEQ ID NO:196, and SEQ ID NO:197, respectively; xx) heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), and heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 199, 200, and 201, respectively; yy) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 203, 204, and 205, respectively; or zz) a heavy chain variable region comprising a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3) having the amino acid sequences set forth in SEQ ID NOs: 207, 208, and 209, respectively; A binding domain, wherein each of the HCDRs may contain up to three, two, or one amino acid substitutions.

17. 17. The binding domain of claim 16, wherein the binding domain comprises a heavy chain variable region having an amino acid sequence set forth in any one of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, or 206, or having at least 80%, or 85%, or 90%, or 95% sequence identity thereto.

18. The binding domain of claim 16 or 17, wherein the binding domain comprises a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) having the amino acid sequences set forth in SEQ ID NO:219, SEQ ID NO:220, and SEQ ID NO:221, respectively, and each of the LCDRs may comprise up to three, two, or one amino acid substitutions.

19. 19. The binding domain of any one of claims 16 to 18, wherein the binding domain comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO:218, or having at least 80%, or 85%, or 90%, or 95% sequence identity thereto.

20. The binding domain of any one of claims 1 to 19, wherein the binding domain is a Fab.

21. A binding moiety comprising two binding domains according to any one of claims 1 to 20.

22. The binding moiety of claim 21 , wherein the binding moiety is an IgG1 or IgG4 antibody.

23. 23. The binding moiety of claim 21 or 22, wherein the binding of the binding moiety to an Fc receptor is eliminated or reduced.

24. 23. The binding moiety of claim 21 or 22, wherein the binding of the binding moiety to an Fc receptor is enhanced.

25. 25. The binding moiety according to any one of claims 21 to 24, wherein the binding moiety exhibits a higher binding signal than a reference antibody comprising two heavy chains having the amino acid sequence set forth in SEQ ID NO:210 and a light chain having the amino acid sequence set forth in SEQ ID NO:

211.

26. 26. A pharmaceutical composition comprising an effective amount of a binding domain according to any one of claims 1 to 20, or a binding moiety according to any one of claims 21 to 25, and a pharma- ceutically acceptable carrier.

27. A binding domain according to any one of claims 1 to 20, a binding site according to any one of claims 21 to 25, or a pharmaceutical composition according to claim 26, for use in therapy.

28. A binding domain according to any one of claims 1 to 20, a binding moiety according to any one of claims 21 to 25, or a pharmaceutical composition according to claim 26, for use in the treatment of cancer.

29. 27. A method for treating a disease comprising administering to an individual in need of treatment an effective amount of a binding domain according to any one of claims 1 to 20, a binding moiety according to any one of claims 21 to 25, or a pharmaceutical composition according to claim 26.

30. 27. A method for treating cancer, comprising administering to an individual in need of treatment an effective amount of a binding domain according to any one of claims 1 to 20, a binding moiety according to any one of claims 21 to 25, or a pharmaceutical composition according to claim 26.

31. A nucleic acid comprising a nucleic acid sequence encoding the heavy chain variable region of claim 16 or 17.

32. 32. The nucleic acid of claim 31 , wherein the nucleic acid further comprises a nucleic acid sequence encoding a CH1 region, and optionally a hinge, CH2 and CH3 region.

33. A cell comprising a nucleic acid sequence encoding the heavy chain variable region of claim 16 or 17.

34. 34. The cell of claim 33, wherein the cell further comprises a nucleic acid sequence encoding a CH1 region, and optionally a hinge, CH2 and CH3 region.

35. 35. The cell of claim 33 or 34, wherein the cell further comprises at least one nucleic acid sequence encoding a light chain variable region.

36. 36. The cell of claim 35, wherein the light chain variable region is a light chain variable region of claim 18 or 19, and optionally a CL region.

37. A cell producing a binding domain according to any one of claims 1 to 20, or a binding moiety according to any one of claims 21 to 25.

38. A kit comprising a container containing a binding domain according to any one of claims 1 to 20 or a binding moiety according to any one of claims 21 to 25, and optionally instructions for use.

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